Reducing inflammation to protect vision for diabetic retinopathy and premature infants
Diabetic retinopathy and retinopathy of prematurity are eye diseases that occur when blood vessels grow uncontrollably and leak fluid and blood into the eye, causing vision loss. Inflammation can be a response to this damage and may make the eye disease worse.
Researchers from the Medical College of Georgia have published a study in the journal Cell Death and Disease, showing that a molecule called arginase 1 may interfere with the inflammatory response and reduce damage. Arginase 1 has been previously studied as a potential treatment for certain types of cancer. In this new study, researchers studied mice who had been fed a high-fat diet and developed a condition similar to diabetic retinopathy. When these mice were treated with arginase 1, the mice had less inflammation and exhibited healthier retinas with less leakage.
Currently, the standard treatment for diabetic retinopathy is injections into the eye of a drug called anti-VEGF which reduces blood vessel growth. These treatments can be very effective at slowing progression of the disease but can also be invasive. What is potentially exciting about arginase 1, is that it can be delivered by a less invasive method.
This is encouraging but still early-stage research. More work will have to be done in animal models before this potential treatment can be tested in humans in a clinical trial. We look forward to learning more as the research progresses.
Clinical trial results for GUCY2D gene therapy for Leber congenital amaurosis
Results from a Phase ½ gene therapy clinical trial for people with Leber congenital amaurosis (LCA), caused by mutations in the gene GUCY2D were announced in October at the American Academy of Ophthalmology Annual Meeting in Chicago. LCA is an inherited retinal disease that leads to severe vision loss or blindness, often from birth. Despite having significant vision loss, people with GUCY2D mutations often retain their retinal structure, including photoreceptor cells, making them potentially good gene therapy candidates.
Data from this trial, which is sponsored by Atsena Therapeutics, was presented for 15 trial participants. Overall, the gene therapy ATSN-101 was well-tolerated. In addition, some of the patients who received the highest dose of ATSN-101 showed improvements in night vision as tested by their ability to respond to different light levels and to navigate a multi-luminance mobility course.
These results are promising and this early-phase trial will continue to treat and monitor participants to determine longer-term safety and efficacy.
FBC-Funded: Exploring vision loss in an animal model of BBS10
FBC-funded researcher Dr. Arlene Drack has published a study in the journal Disease Models and Mechanisms characterizing an animal model of Bardet-Biedl syndrome (BBS) type 10 (BBS10). BBS is a rare genetic syndrome that leads to multiple symptoms, including kidney problems, obesity, and retinal degeneration. BBS can be caused by mutations in more than 20 genes. BBS10 is one of the most common forms of BBS, caused by mutations in the BBS10 gene.
Dr. Drack developed a mouse that did not have a functional BBS10 gene to try and understand more about how mutation of the BBS10 gene leads to vision loss. Examination of this mouse model provided information about how fast vision loss was progressing, as well as what the structure and health of retinal cells were at different stages of retinal degeneration.
The foundational results from this study have provided valuable information that will be used to set up end points for future natural history studies and other pre-clinical work that is needed before a potential treatment for BBS10 can be tested in a clinical trial.
Having retinitis pigmentosa may increase risk of glaucoma
A new study from Taiwan, published in the Journal of Ophthalmology reported that patients with retinitis pigmentosa (RP) have greater risk of developing the most common form of glaucoma, primary open-angle glaucoma, than those without RP.
This was a retrospective study using data from Taiwan’s National Health Insurance Research Database. More than 6,000 patients with RP were identified and they were compared to almost 25,000 patients without RP.
Over the study period, 1.6% of individuals with RP were diagnosed with glaucoma compared to 0.8% of individuals without RP. This study strengthens the case for regular eye exams. It also highlights the importance for clinicians to pay close attention to signs of glaucoma development in patients with RP in order to diagnose and treat the disease as early as possible.
New drug tested in Phase 3 clinical trial for Stargardt disease
A clinical trial has just launched that will test if a drug called Tinlarebant can slow disease progression in Stargardt disease. Stargardt disease is an inherited retinal disease, usually caused by mutations in the ABCA4 gene, that leads to progressive loss of central vision. There are currently no treatments for Stargardt disease.
In this Phase 3 trial (DRAGON), sponsored by Belite Bio, 60 participants will receive Tinlarebant or a placebo-control. In laboratory studies, Tinlarebant inhibits uptake of vitamin A into the retina. This may help reduce the toxic accumulation of vitamin A by-products which are found in Stargardt disease.
The trial has sites in the U.S., Europe, Asia, and Australia and plans to complete in 2024. We will keep you updated about results in the coming years.
Gene therapy approaches for Leber congenital amaurosis and dry age-related macular degeneration successfully tested in laboratory
Two studies have been published which hold promise for development of new treatments for dry age-related macular degeneration (AMD) and Leber congenital amaurosis (LCA).
In the first study, published in the journal Clinical and Translational Medicine, researchers from Trinity College Dublin, developed a new gene therapy approach for dry AMD. Dry AMD accounts for up to 90% of all AMD cases. Often, dry AMD does not have a significant impact on vision. However, in over 10% of cases it can progress to an advanced form (geographic atrophy) or into wet AMD, which can lead to significant vision loss.
In this study, researchers developed a gene therapy to target a part of the cell called the mitochondria. Mitochondria produce energy which fuels cellular functions. In AMD, mitochondria can become damaged and stop working properly. The new gene therapy aims to improve energy generation in mitochondria. The potential therapy has shown promise in animal models of dry AMD.
In the second study, published in Stem Cell Reports, researchers at the National Eye Institute (NEI) in the U.S., developed a gene therapy for LCA caused by mutations in the NPHP5 (also called IQCB1) gene. LCA is an inherited retinal disease that leads to degeneration of light-sensing photoreceptors in the retina. LCA can be caused by mutations in at least 25 different genes. There is currently only one treatment, specifically for individuals with mutations in the RPE65 gene, but no treatment for the other forms of the disease.
Previously it wasn’t clear what the exact role of NPHP5 was in the cell. In this study, researchers showed that mutations in NPHP5 led to loss of the outer segment of photoreceptor cells and disruption of key light-sensing molecules. They also demonstrated that using gene-therapy to put a functional version of the NPHP5 gene back into photoreceptor cells improved the structure of photoreceptor cells.
These are promising results, but these potential treatments are still at a very early stage of development. Further experiments will have to be done in the laboratory before they can be considered for clinical trials.
First patients dosed in clinical trials for retinitis pigmentosa and Stargardt disease.
A phase ½ trial sponsored by Endogena Therapeutics, testing a small molecule called E-2353 as a potential treatment for retinitis pigmentosa (RP) has dosed its first patient. The treatment aims to activate retinal stem cells in the eye which can then develop into new photoreceptor cells (light sensing cells that are damaged and lost in RP and other types of retinal degeneration).
This trial is taking place in the U.S. and will have 14 participants. The main goal of the trial is to test if treatment is safe. If the treatment is found to be safe, larger clinical trials will be necessary to test if the treatment is effective at improving or stabilizing vision. E-2353 is not gene or mutation specific and if successful, may be useful for individuals with many types of inherited retinal diseases (IRD) as well as other types of retinal degeneration.
Nanoscope has also dosed the first patient in a Phase 2 clinical trial testing an optogenetic therapy for Stargardt disease. Stargardt disease is an IRD that causes progressive loss of central vision. The optogenetic therapy, called MCO-010, is for individuals who have lost most of their light-sensing photoreceptor cells. The therapy delivers a light-sensing protein called an opsin to surviving retinal cells called bipolar cells that normally can’t sense light. The new opsin protein allows these bipolar cells to sense and send light signals to create some vision. The trial called STARLIGHT will test the treatment in a small number of patients (approximately six). Nanoscope is also testing MCO-010 in a separate Phase 2b trial for individuals with advanced RP. This trial, called RESTORE, has completed enrollment.
ProQR stopping clinical trials for Leber congenital amaurosis and Usher syndrome 2A
ProQR is a biotechnology company that produces RNA-based gene editing therapies for rare genetic diseases. Unlike gene therapies, these RNA therapies are not designed to be permanent. Instead, people receive new injections of therapy at regular intervals.
In our March 2022 Research News update, we shared that ProQR’s RNA therapy sepofarsen did not significantly improve vision in a Phase 2/3 clinical trial for Leber congenital amaurosis (LCA) caused by a mutation in the CEP290 gene (LCA10). With additional analysis, there was some evidence that the treatment may be effective, but this was not statistically significant based on how the clinical trial was set up. Government regulatory agencies in Europe said that the therapy’s effectiveness had to be proven in an additional clinical trial before sepofarsen could be considered for approval.
Based on this, ProQR announced that as they do not currently have the funding to launch new clinical trials, they are winding down ongoing clinical trials for sepofarsen and for another RNA treatment, ultevursen (QR-421a) for Usher syndrome 2A (USH2A). ProQR is actively looking for a partner to help fund these programs and enable the launch of additional clinical trials to meet regulator recommendations.
ProQR will work with clinical trial participants, including those in Canada, to try and offer them continued access to sepofarsen or ultevursen therapy. At Fighting Blindness Canada, we will continue to monitor the status of these therapies and will inform you if clinical trials are restarted.
Intermittent fasting may reduce the risk of developing age-related macular degeneration (AMD)
Individuals who fast may have a reduced risk of age-related macular degeneration (AMD) according to a new study published in the American Journal of Ophthalmology. In this Korean study, 4504 participants (aged 55 years or older) underwent eye examinations and self-reported on their meal frequency. 4% of participants reported not eating breakfast and they were categorized as intermittent fasters. 14% of participants in the intermittent fasting group had AMD compared to 26% of participants who did not fast. In particular, fasting reduced the risk of AMD in individuals who were younger (less than 70 years of age), had obesity or lived in urban areas compared to similar populations who did not fast.
It is not clear why fasting might reduce AMD risk, although fasting or calorie restriction has previously been shown to be neuroprotective in laboratory studies. Further studies that are larger and/or are prospective will be important to better understand the role that calorie consumption and fasting may have on AMD risk and progression.
This August we are excited to share three research advances that would not have been possible without FBC funding.
Moving towards Stem Cell Therapy for Inherited Retinal Disease and Age-Related Macular Degeneration
Stem cells hold the promise of being able to restore vision for many types of retinal degenerative diseases, including inherited retinal diseases like retinitis pigmentosa and age-related macular degeneration. However, there are still many challenges such as low survival and integration of transplanted cells.
In a new study funded through a FBC Restore Vision 20/20 grant, Dr. William Beltran (University of Pennsylvania) and Dr. David Gamm (University of Wisconsin) have overcome some of these significant challenges, moving this research one step closer to a potential clinical trial.
Published in the journal Stem Cell Reports, the researchers developed a robust transplantation methodology which they tested in the eyes of dogs. This involved developing a new way to inject cells under the retina and an immunosuppression regimen to prevent rejection of transplanted cells. Following this procedure, the team was excited to see that transplanted cells not only survived in the retina but also appeared to form connections with other remaining cells. This last step is crucial if new transplanted photoreceptors are going to be able to pass light signals on to other cells in the retina and finally to the brain to form images.
This FBC-funded project is ongoing, and the next stage is to continue to optimize the procedure and test if transplanted cells restore some vision in the animal model.
Clinical trial launched to test small molecule therapy for retinitis pigmentosa
Kiora Pharmaceuticals received authorization to launch a Phase 1B clinical trial to test a small molecule (KIO-301) for people with advanced retinitis pigmentosa (RP) and potentially other types of retinal degeneration.
In RP and other types of retinal degeneration, photoreceptor cells, which sense light, are damaged or die, leading to vision loss. KIO-301, is a light-sensitive molecule called a “photoswitch” which can turn other remaining retinal cells (in this case retinal ganglion cells) into new light sensors, potentially replacing the function of lost photoreceptor cells. This is similar to optogenetics, in that non-light sensing cells are being turned into light-sensors. However, light-sensitivity is not being created by a gene but in this case by a small molecule, which will need to be administered on a regular basis. This means the procedure is not permanent and offers the potential to optimize things such as drug formulation and dosing over time.
The clinical trial, called ABACUS (ClinicalTrials.gov identifier: NCT05282953), will take place in Australia and hopes to begin enrolling patients in 2022.
FBC supported development of related photoswitch molecules through a Restore Vision 20/20 research award to Dr. Richard Kramer (University of California Berkley).
Dr. Kramer will be presenting about this and other vision restoring research at FBC’s upcoming View Point Toronto on October 2, 2022. Book your View Point education event seat!
Understanding the impact of an inherited retinal disease for Canadians
In July, FBC published a study in the Canadian Journal of Ophthalmology about the physical, emotional and practical challenges that individuals with an inherited retinal disease (IRD) face in Canada.
The study was based on an online survey that asked questions about self-reported vision, genetic testing, health care experiences and disease impact on daily life. The survey was developed by FBC and data was analysed by Dr. Cynthia Qian and Imaan Kherani.
Survey respondents identified having 1 of more than 14 IRDs, with 72% specifying retinitis pigmentosa. 68% reported being legally blind, and more than 85% self-reported moderate to low vision or worse. IRDs impacted daily functioning, with 53% of respondents indicating that their eye disease affected their employment or education. Psychological challenges were evident, with more than 70% worried about coping with daily life, and more than 60% indicating fear and stress. Interviews with individual respondents identified feelings of hopelessness around finding suitable work, loss of independence, and challenges with social interaction with 65% reporting a negative impact on family life. Notably, many had not accessed social support services because of a lack of perceived need, awareness, or availability.
This study was based on responses from over 400 of our community members and we thank all who participated for generously sharing their experience with us and the wider medical and scientific community. This information collected provides a deeper perspective and understanding into what it means to live with a rare and progressive eye disease. It will be a powerful tool as we engage with government, health, and regulatory bodies to improve care and treatments for Canadians living with an IRD.
Leber hereditary optic neuropathy (LHON) gene therapy clinical trial update
A phase 1 gene therapy trial for Leber hereditary optic neuropathy (LHON) was found to be safe but did not improve vision or slow vision loss.
LHON causes sudden loss of central vision, usually in young adulthood. It is caused by mutations that disrupt the function of mitochondria. Mitochondria are cellular components that produce most of the energy in the cell and power cellular functions. This clinical trial was trying to restore the function of mitochondria by adding back a functional version of the ND4 gene. Mutations in ND4 are responsible for approximately 60-70% of cases of LHON.
Led by Dr. Bryan Lam (Bascom Palmer Eye Institute, University of Miami), the trial followed 28 patients who received different doses of the gene therapy for an average of 2 years. The results, published in the American Journal of Ophthalmology, demonstrated the safety of the treatment. Uveitis was the most notable side effect of treatment, and it was more likely to occur in patients who received higher doses of the gene therapy.
Unfortunately, even though the treatment appears safe, it did not prevent vision loss. Some individuals did experience some vision improvement but the effect was not consistent and was at best modest. Based on these results the research team will not test this gene therapy in further clinical trials.
Another ND4 gene therapy, LUMEVOQ, by GenSight Biologics has been submitted for approval by the European Medicine Agency and is also undergoing additional testing in an ongoing Phase 3 clinical trial.
Choroideremia gene therapy clinical trial update
An ongoing phase ½ gene therapy clinical trial for choroideremia published two-year results in the journal Ophthalmology. The trial, sponsored by Spark Therapeutics treated one eye of fifteen patients between the ages of 20 and 57 years.
The results showed that overall there were no systemic toxicities. There has been concern that subretinal injections could harm the already delicate retina in individuals with choroideremia. In this trial, visual acuity dropped immediately after treatment but it returned to baseline in all but two patients. One patient experienced thinning at a specific part of the retina, while the other developed a macular hole.
These are interim results and results from longer observation will be important to see if there are any positive impacts from the gene therapy treatment. The side effects that occurred in the two patients will also have to be considered to determine if there are better ways to deliver gene therapy to reduce any risk of retinal damage in individuals with choroideremia.
A new report looking at 10 years of data, suggests that the AREDS2 formula is slightly more effective compared to the original AREDS formulation.
The original Age-Related Eye Disease Studies (AREDS) demonstrated that dietary supplements can slow the progression of age-related macular degeneration (AMD) from moderate to late disease. However, other studies showed that individuals who smoked and took beta-carotene (which was a component of AREDS) had an increased risk of lung cancer. Therefore, a new formulation, AREDS2 that contained the antioxidants lutein and zeaxanthin instead of beta-carotene was tested. Five-year data from this study, published in 2013, showed that AREDS2 also reduced the risk of AMD progression and did not increase lung cancer risk.
In this new study published in JAMA Ophthalmology, researchers looked at longer-term data. This data showed that indeed the “new” AREDS2 formulation did not increase the risk of lung cancer. Interestingly, there was also a small (20%) reduced risk of progression to late AMD compared to individuals who started the study taking the original AREDS formulation. This study confirms that AREDS2 is safe for smokers or those at higher risk of lung cancer. It also suggests that taking AREDS2 may offer a small added benefit over taking AREDS.
If you have questions, speak to your eye doctor before starting or changing your supplements to understand what is best for you.
1 in 3 individuals with diabetes are not receiving regular eye screening for diabetic retinopathy
A new retrospective study published in the Canadian Journal of Ophthalmology, shows that many individuals with diabetes are not receiving regular eye screening in Ontario. Diabetic retinopathy is an eye condition that can cause vision loss and blindness in people who have diabetes. It is important to have regular eye exams, to identify early signs of diabetic retinopathy and start treatment early, to prevent vision loss. In Ontario, individuals who have diabetes are eligible for free annual eye exams. However, many do not know this or are not able to easily access screening.
In this study, led by Dr. Tina Felfeli, a Fighting Blindness Canada Clinician-Scientist Emerging Leader awardee, a population-based approach was used, analyzing health records from all adults with diabetes (type 1 and type 2) between 2011-2013 and 2017-2019. It showed that 33% of individuals with diabetes did not receive diabetic retinopathy screening in a 10-year period. Individuals who were younger (aged 20-39), had lower incomes, lived in urban areas, were recent immigrants or had a history of mental health challenges were more likely to miss screening.
This study shows the need for better strategies to improve eye care uptake, especially among populations in greatest need. Fighting Blindness Canada is a proud supporter of Project Open which is trying to tackle this problem of underscreening and health inequity. Read more.
Recap from ARVO: the latest in vision research
In May, FBC attended the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in Denver, Colorado for 5 days of learning and discussion with leaders in vision research.
We heard about advances in vision research and learnings from clinical trials for innovative treatments.
Could a drug that treats alcoholism help improve vision in retinitis pigmentosa?
New research from FBC-funded researcher Dr. Richard Kramer (University California, Berkley) shows a potential way to improve vision in individuals who have retinal degeneration using the drug disulfiram (Antabuse).
Vision loss in many types of retinal degeneration, including most inherited retinal diseases (IRDs) like retinitis pigmentosa (RP) and age-related macular degeneration, is caused by the death of light-sensing photoreceptor cells. When photoreceptor cells die, they release a chemical compound which is converted into retinoic acid. Dr. Kramer previously showed that high levels of retinoic acid lead to constant activation of the optic nerve, which sends light signals to the brain. This creates a type of “background noise” that makes it hard for the optic nerve and brain to react to real light signals.
In this study, published in the journal Science Advances, Dr. Kramer’s team used disulfiram, which has been used to treat alcoholism, to reduce retinoic acid levels in a mouse model of RP. They found that mice with RP had better visual responses after treatment with disulfiram. Based on these results, the team wants to launch a small clinical trial to see if this drug would have the same impact in patients. This treatment is not likely to reduce the progression of retinal degeneration, however, it might help people maximize the vision they have left.
While the results seem promising another study published in eLife suggests that the role of retinoic acid in vision may be more complicated. There are two types of photoreceptor cells, cones (responsible for detail and central vision) and rods (responsible for night and peripheral vision). In RP and many other IRDs, rod cells are damaged and die first and cone cell death appears to be a secondary effect of disease progression. The eLife study led by researchers at Harvard Medical School found that reducing retinoic acid in a mouse model of RP led to reduced cone photoreceptor cell survival.
Taken together, these studies show that retinoic acid may play multiple and potentially conflicting roles in retinal degeneration and vision loss. More work will be important to better understand this complexity.
Anti-VEGF biosimilar approved by Health Canada for macular degeneration and diabetic macular edema
BYOOVIZ the first anti-VEGF biosimilar for ranibizumab (Lucentis) has been approved for use in Canada.
Anti-VEGF drugs help slow the growth of abnormal blood vessels and can reduce vision loss in wet age-related macular degeneration, diabetic macular edema and other diseases. Anti-VEGFs are a type of drug called a biologic, made of complex molecules that are synthesized in living systems like cells. Biologics differ from many common drugs like Tylenol or Claritin that can be manufactured by simply combining different chemicals. A biosimilar is a “generic” form of a biologic. A biosimilar should have the same medical effect as the original biologic but unlike a generic drug, might not be identical in composition and structure to the original drug.
BYOOVIZ is distributed by Samsung Bioepis and Biogen. Health Canada approval of BYOOVIZ was based on both quality control data and clinical data, including a randomized phase 3 study. In this trial, the safety and efficacy of BYOOVIZ was found to be similar to the original biologic, ranibizumab. BYOOVIZ was approved in the US and Europe in 2021.
Similar to generic drugs, biosimilars are often less expensive than the original drug offering cost savings to the health care system. If your doctor recommends switching your anti-VEGF treatment to an alternative biologic or biosimilar you can ask if this will impact your treatment schedule or vision. You should always feel comfortable asking questions about the treatment you are receiving.
FBC Funded Research: Developing Cone Photoreceptors from Stem Cells
Cone photoreceptor cells are responsible for central and detail vision. Much of this type of vision is initiated within a specialized region of the retina called the fovea. Damage and death of foveal cone cells is responsible for central vision loss in many retinal diseases including Stargardt disease and age-related macular degeneration.
Published in the journal Cell Stem Cell, Dr. Gamm and Dr. Raunak Sinha, demonstrated for the first time that cone photoreceptors derived from stem cells could respond to light and generate light signals similar to normal cone cells in the eye. This is an important step toward developing a stem cell replacement therapy to restore central vision.
In this study, partially funded by FBC, the team from the University of Wisconsin-Madison, developed 3-dimensional cell structures called organoids in the laboratory. The organoids are composed of retinal cells including cone photoreceptors. Until now, scientists haven’t been able to generate photoreceptors that produce light signals as strong as seen in a healthy retina. Drs. Gamm and Sinha believed that growing cones within an organoid structure would improve their ability to develop into functional photoreceptors.
The researchers grew the organoids for over 8 months to ensure the cells had enough time to mature into functional photoreceptors. When tested, these organoids produced strong light responses similar to those seen in the fovea of animal models. The organoid cells could also distinguish between different colours of light just like normal human cone cells do.
The team will now try to improve on these results with the ultimate aim to translate this research into new treatments for different types of retinal degeneration.
Dr. Gamm was the recent recipient of a $750,000 award from FBC through the Restore Vision 20/20 program to further develop a stem cell therapy. Learn more.
Second Sight, no longer supporting Argus II Retinal prosthesis
The Argus II was the first, and currently only, retinal prosthesis approved in Canada. It provides a form of artificial vision for individuals with advanced retinitis pigmentosa. The Argus II (and predecessor Argus I) were developed and sold by Second Sight. Second Sight will no longer be supporting the Argus II, leaving individuals who have the retinal prosthesis with an uncertain future.
In 2019 Second Sight discontinued the implant and in 2020, following financial difficulties, turned its focus to a brain implant called Orion. Orion also provides artificial vision but has the potential to be useful for individuals who are blind due to a wide range of causes beyond retinitis pigmentosa. Orion is currently being tested in an early feasibility study supported by the National Institutes of Health (NIH). In February, Second Sight announced they were merging with Nano Precision Medicine. Following the merger, it is unclear what the future is for further development or clinical trials involving Orion.
What does this mean for individuals who already have Argus retinal implants? This is explored in a long-form article in the electrical engineering magazine IEEE Spectrum. While many remain grateful for their retinal devices and continue to use them, there is also concern that following recent changes to the company there will not be appropriate or available support if the devices stop working or need to be removed. According to an article in the BBC, Second Sight has said it will do its best to “provide virtual support” but will not provide repairs or replacements for the implants.
This story offers both hopeful and cautionary messages. The Argus II was a ground-breaking technology that offered patients who were blind the first opportunity to restore some vision, although a very artificial form of vision. While the company has moved on from the Argus II it did pave the way for other companies to develop retinal and brain implants. There are different models at various stages of development which aim to provide more functional vision. However, it also provides a reminder of the risks that patients face if they come to rely on an implant or piece of technology, as there is no guarantee that long-term support or improvements will be available if a company changes focus or goes out of business.
This topic was covered on CBC’s radio program The Current on March 7, 2022. Listen to “What happens when the technology behind a ‘bionic eye’ becomes obsolete?”
LCA10 Gene Therapy Sepofarsen Does not Show Vision Improvement in Phase 2/3 Clinical Trial
ProQR biotechnology company has announced that the RNA therapy sepofarsen did not significantly increase best-corrected visual acuity (BCVA) in a Phase 2/3 clinical trial. The potential treatment was tested in 36 individuals with Leber congenital amaurosis (LCA) caused by the p.Cys998X mutation in the CEP290 gene (LCA10).
Results from an earlier Phase ½ clinical trial showed improvement in vision in a small number of individuals up to 12 months after being treated with sepofarsen. This led ProQR to launch this larger Phase 2/3 study, called Illuminate, in 2019. This was a randomized clinical trial with participants being randomly assigned to two different treatment groups or a sham injection group (e.g. placebo group).
Disappointingly, in this larger study, there was no significant difference in BCVA between patients who received sepofarsen and those who did not. There was also no difference in other tests such as full-field stimulus test or mobility. ProQR has said they will continue to analyze the data. The current results make the future of sepofarsen as a potential therapy for LCA10 unclear. Sepofarsen is currently also being tested in a Phase 2/3 study, called Brighten, for children with LCA10 who are under 8 years old.
Study finds that up to 30% of patients with wet AMD may be able to stop anti-VEGF injections
In a new study from Johns Hopkins Medicine, almost a third of patients with wet age-related macular degeneration (AMD) were able to safely stop anti-VEGF injections.
AMD is the most common cause of vision loss in people over the age of 50. There are two forms of AMD, wet and dry. The wet form is responsible for most of the vision loss caused by AMD. In wet AMD, uncontrolled blood vessel growth and fluid leaking into the eye leads to vision loss. The most common treatment for wet AMD is injections of anti-VEGF (anti-vascular endothelial growth factor) drugs into the eye which can prevent and in some cases restore some vision. However, having to receive monthly or bi-monthly injections can be very challenging and stressful for patients.
This study, published in the Journal of Clinical Investigation followed 106 people who each received a customized injection schedule. Patients were monitored at each visit to see if they could pause injections. Within one year, approximately 31% of patients had stopped treatment, with the majority of these patients remaining treatment-free for up to two years. Patients were considered to be safely weaned off anti-VEGF treatment if they went at least 30 weeks without an injection, without having fluid accumulating in the eye or worsening vision loss.
The researchers also analyzed fluid from patient eyes and found 172 molecules that were different between those who safely stopped treatment compared to those who continued with monthly injections. The researchers will continue to study these molecules to try and identify biomarkers that may help predict which patients can stop treatment early.
This study raised some very interesting possibilities for the future of wet AMD treatment. However, because the study was so small it is still too preliminary to change clinical practice. The next step will be to perform a randomized trial to test if the same results are seen with a larger group of patients. If so, in the future it could give some patients the opportunity to safely pause or stop anti-VEGF injections while still maintaining eye health.
Research paving the way for Stargardt disease clinical trials
Two pieces of news this month offer hope for individuals with Stargardt disease that new and improved clinical trials are on the way.
Researchers at the National Eye Institute (NEI) have developed an artificial intelligence-based method to measure Stargardt disease progression. Stargardt disease, an inherited retinal disease, can progress very differently for different people and may depend on the type of genetic change that is the cause of the disease. The research team used OCT imaging along with deep-learning methods to detect patterns in retinal structure in patients with different gene variants. This work, published in the Journal of Clinical Investigation Insight, gives researchers a sensitive way to measure disease progression in Stargardt disease. This will have important implications for future clinical trials, providing a new and reliable tool to help researchers measure if a new therapy is working and slowing down disease progression.
In other exciting news, Nanoscope announced they had received clearance from the FDA to begin a Phase 2 clinical trial testing an optogenetic therapy (MCO-010) for Stargardt disease. In this treatment, a gene called multi-characteristic opsin (MCO) is delivered to retinal cells using a gene therapy approach. MCO turns non-light sensing retinal cells into light sensors to replace lost or damaged photoreceptor cells. Nanoscope hopes to launch this new trial in 2022. Nanoscope is already testing the same treatment in a Phase 2b trial for retinitis pigmentosa (RP). Results from an earlier Phase 1/2 trial demonstrated that the treatment was safe and participants with RP had improved functional vision such as shape discrimination and mobility tests. Learn more about optogenetics.
ReNeuron halts work on cell replacement therapy for retinitis pigmentosa
ReNeuron has announced its decision to stop work and financial support on a human retinal progenitor cell (hRPC) therapy for retinitis pigmentosa (RP). The potential treatment was tested in a Phase 2a clinical trial. Based on inconclusive trial results, ReNeuron has decided that it will no longer invest in this product.
The cell replacement therapy involved injecting progenitor cells (cells that have capacity to develop into different cell types) into the eye. The hope was that the progenitor cells would integrate into the retina and develop into light-sensing photoreceptor cells, replacing photoreceptors lost during RP progression. The therapy was first tested at a low dose. When this was shown to be safe, the therapy was tested at a higher dose. Unfortunately, injecting a higher number of cells led to more surgical complications and ultimately some patients experienced some loss of vision. Analysis of data from patients who received the lower dose showed an overall improvement in vision at 12 months after treatment, but this decreased by 24 months.
Based on the limited results seen ReNeuron said that they were not prepared to invest further in this treatment at this time.
Cataract surgery linked to reduced risk of developing dementia
Cataract surgery is a common procedure for older adults with cataracts to help prevent vision loss. A new study published in JAMA Internal Medicine shows that cataract removal may have wider health benefits and could help reduce the risk of developing dementia.
Researchers from the University of Washington analyzed data from over 3,000 participants in a longitudinal study. At the start of the study participants did not have cataracts. Over the course of the study approximately half of the participants received cataract surgery and 853 participants developed dementia. The data showed that individuals who had cataract surgery were about 30% less likely to develop dementia in the 10 years after surgery.
It isn’t clear exactly why this link between cataract surgery and dementia exists but the research team gave some possible reasons. Vision loss may cause people to limit social activity and exercise. Decrease in these activities are linked to cognitive decline. As well, the way cataracts impact vision could lead to specific changes in the brain or impact the way sensory input is received by the brain. Regardless of the reason, this study provides strong evidence that helping people maintain vision as they age is crucial for healthy aging and better quality of life.
Beovu, a new therapy for age-related macular degeneration, funded for use in two provinces
Novartis announced in December that a new anti-VEGF injection brolucizumab (brand name Beovu) is now funded by the Ontario and New Brunswick Drug Plans for treatment of wet age-related macular degeneration (AMD). Anti-VEGF injections are the standard of care for wet AMD, helping prevent further vision loss and in some cases restore some vision. Beovu is a new anti-VEGF that allows patients to delay the time between injections. After the first few doses, eligible patients can be put on a once every three-month treatment schedule. Novartis will be working with other provinces to increase access to this treatment for more Canadians.
PREVIOUS RESEARCH NEWS
BRAIN IMPLANT PROSTHESIS RESTORES SOME SIGHT
A new prosthesis device has allowed a former teacher, who had been blind for 16 years, to see letters, identify edges of objects, and even play a simple video game. This study, a collaborative project between American and Spanish researchers, was published in The Journal of Clinical Investigation.
In this study, a microchip was implanted into the visual cortex, the part of the brain that processes visual information, and then paired with a video camera attached to a pair of glasses. The volunteer, Berna Gomez, had lost her vision due to optic neuropathy and before testing the prosthesis had no light perception. However, after undergoing a period of training, some of Berna’s functional vision was restored. Berna was also named as an author on the study, because of her contribution to the research.
Notably, the implant did not cause any severe side effects or disruption of other brain activity. While some of the improvements were limited, for example, Berna could only reliably identify some letters of the alphabet, the study gives researchers hope that the device could meet its goal, which is to improve mobility, independence and safety of individuals who are blind.
A clinical trial related to this study is ongoing, and will test the device in five individuals over the next 3 years.
UNDERSTANDING DRUSEN FORMATION IN AGE-RELATED MACULAR DEGENERATION (AMD)
Geographic atrophy is a form of advanced dry age-related macular degeneration (AMD). It is associated with a protein deposit called drusen. While it is not clear what role drusen plays in disease progression or how it is made, increased deposits often appear before the development of geographic atrophy. A study published in the Journal of Extracellular Vesicles has shed some light on the early appearance of drusen.
Retinal pigment epithelial (RPE) cells, which sit under and provide support for light-sensing photoreceptor cells, were shown to release drusen under normal conditions. This increased dramatically when cells were exposed to stress conditions, similar to what might be found in AMD. This is the first evidence that RPE cells may be actively making and releasing drusen, as opposed to being a by product from damaged cells. The researchers speculate that drusen formation and release is a response to stress conditions. In the future, this information may help researchers diagnose geographic atrophy earlier and possibly find ways to reduce the amount of drusen that is released.
TESTING PROZAC AS A POTENTIAL TREATMENT FOR DRY AMD
Researchers at the University of Virginia have evidence that the antidepressant fluoxetine (Prozac) could be a treatment for dry age-related macular degeneration (AMD). 8 out of 10 people who have AMD have dry AMD, which occurs when parts of the macula, the central part of the retina, get thinner and damaged. Dry AMD can lead to vision loss if it progresses to geographic atrophy or wet AMD.
Published in the journal PNAS, researchers tested fluoxetine and eight other anti-depression drugs in an animal model of AMD. Only fluoxetine reduced the progression of AMD. They then analyzed data from two large insurance databases and found that people who took fluoxetine developed dry AMD more slowly than people who were not on the drug. This is very interesting research but it’s too early to know if Prozac is an effective treatment for dry AMD. The researchers hope that this work will encourage further research including the launch of a clinical trial to test robustly if fluoxetine could be repurposed as an AMD drug in the future.
HOW VISION LOSS CAN AFFECT BRAIN HEALTH
A study published in the journal JAMA Network Open found a link between vision loss and cognitive declines over time. The researchers followed 1202 people, aged 60-94, for an average of seven years and found that people who had poor visual acuity or other vision issues at the beginning of the study were more likely to experience cognitive decline, such as problems with memory, language or attention. Other studies have also seen this association between vision loss and brain health.
The study suggests that when people experience vision loss, they change the way they live, including reducing physical activity and socializing which are important for brain health. Researchers say that this underlies the importance of having regular eye checkups to catch eye problems early and treat them. This is especially key if you have a condition such as glaucoma or diabetes that puts you at high risk of vision loss. For individuals with no treatment or who have already lost vision, low vision rehabilitation and support services can help adapt your home and your life to maintain activity and independence.
YOUR IMPACT: FBC FUNDED RESEARCHERS SHED LIGHT ON CAUSES OF USHER SYNDROME (USH1) AND STARGARDT DISEASE
This month we are happy to report on advances published by two researchers who have been funded by Fighting Blindness Canada (FBC)!
Dr. Vince Tropepe (University of Toronto), who FBC currently funds, published a study in the journal Disease Models & Mechanisms which sheds some light on a potential cause of USH1. This is an inherited disease that leads to hearing and vision loss in children. The team is studying the impact of mutations in the gene pcdh15b, which occur in many cases of Ush1. Using a zebrafish model, Dr. Tropepe’s team showed that mutations in pcdh15b changed the structure of light sensing photoreceptor cells. Interestingly, at early stages the photoreceptors were not dying suggesting that vision loss was likely caused by a loss of function of the photoreceptor cells. This study was the first genetic model of pcdh15-associated retinal degeneration. Dr. Tropepe’s project is ongoing and in the next stage he will be identifying other molecules and networks that work with pcdh15b to maintain photoreceptor function.
Dr. Robert Molday (University of British Columbia), a researcher FBC has been proud to support in the past, has shed some light on the molecular architecture of the protein ABCA4. The gene that provides the instructions to make ABCA4 protein is mutated in most cases of Stargardt disease. ABCA4 is a type of protein called a transporter. Transporters move molecules into and out of cells. When ABCA4 is mutated and stops working in photoreceptor cells, toxic products build up in the cell leading to photoreceptor damage and death and ultimately vision loss.
In this study published in Nature Communications, Dr. Molday’s team used cryo-electron microscopy to understand how ABCA4 protein structure changes when bound to a molecule. They identified specific parts of the ABCA4 protein which are crucial for binding, and interestingly, many of these parts are mutated in Stargardt’s Disease. This study helps explain how some Stargardt disease mutations block the function of ABCA4 leading to vision loss. The hope is that this information can be used to develop drugs that can improve the way ABCA4 works in individuals with Stargardt disease.
GENE THERAPY CLINICAL TRIAL UPDATES FOR LCA10 AND X-LINKED RETINITIS PIGEMENTOSA
A new month brings a new season and some clinical trial updates!
The first update is for the Phase 1/2 clinical trial for a CRISPR-based gene editing treatment (EDIT-101) for Leber congenital amaurosis type 10 (LCA10). LCA10 causes severe vision loss in early childhood and is caused by a splice-site mutation in the CEP290 gene.
The trial is sponsored by Editas Medicine Inc. who announced positive early results from this trial focused on making sure the treatment is safe. Notably, there were no severe side effects reported from the six treated patients. There was also early evidence that the treatment may be improving vision for some patients, three to six months following treatment. This included improvements in best-corrected visual acuity, retinal sensitivity and mobility navigation. Because so few patients are treated in Phase ½ trials, it’s too early to conclude that the treatment works. However, based on these promising results, Editas has started enrolling more patients in the trial and will be testing out a higher dose of the treatment.
MeiraGTx also provided an update on their Phase ½ clinical trial testing a gene replacement therapy for X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene. At twelve months after treatment, the eye that received the gene therapy showed no loss in vision as measured by retinal sensitivity and retinal field, while the untreated eye had continued retinal degeneration. MeiraGtx and Janssen Pharmaceuticals are now recruiting for a larger Phase 3 trial which will provide more data on the effectiveness of this gene therapy.
Finally, AGTC has announced that they are recruiting male participants between the ages of 8-50 for a clinical trial testing gene therapy for XLRP. Visit their website to learn more about the trial. If you are interested in participating, we always recommend discussing with your eye doctor before signing on to a clinical trial.
CLINICAL TRIAL: RESULTS TESTING TREATMENT FOR GEOGRAPHIC ATROPHY
Apellis Pharmaceuticals announced results from their Phase 3 trial, testing a potential treatment (pegcetacoplan) for geographic atrophy (GA). GA is an advanced form of dry age-related macular degeneration (AMD) which causes progressive vision loss. There is currently no treatment or cure for GA. This trial tested if pegcetacoplan could reduce the progression of GA, as measured by the area of the retina that was affected by GA. Conflicting results were announced from two large studies sponsored by Apellis. In one study, researchers saw a significant reduction in GA progression compared to non-treated eyes. However, the second study did not show this reduction and it is not clear why there was this discrepancy. Apellis has said they will submit their drug for approval to the FDA, although the difference in results between the two studies might complicate the approval process.
DEVELOPING A ROBOTIC WHITE CANE TO IMPROVE INDOOR NAVIGATION
Researchers from Virginia Commonwealth University have published details of a new “white cane” equipped with a computer, 3-D camera and measurement sensor to improve indoor navigation. The researchers were trying to create a device that could have the same impact for white cane users as GPS-based navigation has had for sighted individuals. This device tackled a challenge many blind users have in navigating large indoor spaces, especially when the area is unfamiliar. The white cane combines information from the camera and sensors with architectural data from building floor plans to provide better navigation. Unfortunately, the current product is not yet ready for market-for one thing it’s too heavy for regular use. However, researchers are now looking for ways to streamline the device and hope that soon this device could be an essential tool to improve both the navigation and independence of its users.
BIOMARKERS TO HELP DIAGNOSE DIABETIC RETINOPATHY (DR) AND AGE RELATED MACULAR DEGENERATION (AMD) EARLIER
A biomarker is a biological signal that tells scientists if a normal or abnormal process is happening. Across many disease areas, researchers are trying to identify biomarkers that will help diagnose diseases earlier or provide earlier indications that a treatment might (or might not) be working, with the hope that this leads to better outcomes.
This month, we’re sharing two studies that have identified potential biomarkers that could lead to earlier diagnosis of diabetic retinopathy (DR) and age related macular degeneration (AMD).
In the first study, published in the journal Plos One, researchers from Indiana University used artificial intelligence (AI) to see if they could detect DR earlier. Diabetes can cause damage to the eyes before this can be detected by an eye exam. Using AI analysis of retinal images, researchers were able to identify diabetic eyes based on changes that the computer could detect earlier than they would have been able to during a clinical exam.
The second study published in the American Journal of Human Genetics, researchers at Queen Mary University of London identified five proteins that regulate the immune system that are higher in people who have AMD. These proteins are related to another protein, Complement Factor H which was previously shown to be associated with AMD risk. This study suggests that there are additional proteins that might be important and in the future might lead researchers to be able to predict who is at risk of developing AMD even before symptoms have started.
The next step for these studies is to test if they are able to effectively predict disease earlier in large populations and importantly, if this improves outcomes over traditional diagnosis methods.
RETINA CAN PREDICT THE PATH OF MOVING OBJECTS
Researchers at the University of Washington have shown that the retina can create the information needed to predict the path of a moving object before visual signals even leave the eye. Knowing how the retina senses and transmits visual signals will help scientists develop technologies that may restore more meaningful vision for individuals who have advanced vision loss.
Published in the prestigious journal Nature Neuroscience, Dr. Manookin led a team, which included two lead authors who were undergraduate students!
Dr. Manookin’s team studied how light signals are passed from hundreds of cone photoreceptors to dozens of bipolar cells to a small number of retinal ganglion cells (RGC) in an animal model. RGCs make up the optic nerve which sends light signals to the brain. The brain uses this information to create vision and as this paper shows, predict where a moving object will go. The researchers found that when a bipolar cell receives a light signal it communicates this to neighboring bipolar cells, so when they receive a signal they are already “primed” and are able to receive and transmit visual signals more strongly and quickly. This series of signals is sent to the brain and allows the brain to predict when an object is going. Impressively, the RGCs were almost as effective at sending predictive data as a computer program.
As researchers are developing innovative treatments to restore vision, including artificial retinas and retinal prostheses, studies like this may help them create technologies that provide more functional and effective visual outcomes.
NEUROPROTECTIVE GENE THERAPY MAY PREVENT GLAUCOMA VISION LOSS
Scientists at Mount Sinai Hospital in New York have shown that a new gene therapy can protect optic nerve cells and preserve vision in an animal model of glaucoma. Published in the high impact journal Cell, this may be a novel therapy to protect the optic nerve for individuals with glaucoma.
Glaucoma is caused when high eye pressure causes damage to the retinal ganglion cells that make up the optic nerve. These cells are responsible for sending light signals from the retina to the brain where images are formed. While there are a number of treatments and therapies that can control eye pressure, they don’t work for all people and for many this will lead to vision loss or blindness. This research is attempting to find a way to protect the optic nerve from irreversible damage.
In this study, researchers showed that CaMKII protein activity was decreased whenever retinal ganglion cells were damaged. They also found that if CaMKII was turned on using a gene therapy approach just before or after retinal ganglion cell injury, the cells survived much better, showing that CaMKII was neuroprotective. Mice that received the CaMKII activating gene therapy showed improved visual activity and function as measured by tests like electroretinograms (ERG) and functional behaviour tests.
The hope is that this type of therapy could protect integral retinal ganglion cells and make them more resistant to glaucoma-induced damage. This was a very strong example of discovery research and we eagerly look forward to learning more about this potential treatment and if it can transition from the laboratory towards research in other animal models, or a clinical trial in the coming years.
VITAMIN A DRUG DESIGNATED AS BREAKTHROUGH THERAPY FOR STARGARDT DISEASE BY FDA
ALK-001, a chemically modified vitamin A drug for Stargardt disease was granted breakthrough status by the FDA in the United States. This designation is for drugs where preliminary clinical evidence shows there may be substantial improvement for individuals with serious conditions and is meant to speed the development and review of new treatments.
Stargardt disease is an inherited retinal disease that causes progressive vision loss. It affects the macula, the small, central portion of the retina, leading to loss of central vision over time. Stargardt disease affects between 1 in 8,000 to 1 in 10,000 people and vision loss usually begins in childhood or adolescence. Because the symptoms are similar to age-related macular degeneration (AMD), Stargardt disease is sometimes called juvenile macular degeneration.
In Stargardt disease, there is an accumulation of toxic vitamin A clusters in the retina. ALK-001 is vitamin A that has been changed so that it doesn’t form clusters as easily. In an animal model, treatment with ALK-001 slowed the formation of vitamin A clusters and reduced progression of Stargardt disease.
Results from the Phase 2 clinical trial in humans, sponsored by Alkeus Pharmaceuticals, Inc., have not been published yet, but the company said the treatment showed significant effect and they have shared data with the FDA to receive the breakthrough designation. A Phase 3 trial is also ongoing studying the impact of ALK-001 on geographic atrophy caused by AMD.
Breakthrough designation does not mean that a treatment is approved for use. Once a treatment has received breakthrough designation, the FDA will work with the drug’s sponsor to design clinical trials that are as efficient as possible (i.e. minimizing the number of patients who have to participate). Drugs still have to meet rigorous safety standards to ensure that they are safe for use. With this designation, we hope that Phase 3 trials for Stargardt disease will be able to move ahead quickly, with a hope to bringing a new treatment to market as soon as possible.
CLINICAL TRIALS ROUNDUP FOR INHERITED RETINAL DISEASE (IRDS)
This month there are a number of IRD clinical trial updates….
BIOGEN PHASE 3 GENE THERAPY TRIAL FOR CHOROIDEREMIA
There was disappointing news from Biogen who announced that a Phase 3 gene therapy trial for choroideremia did not result in significant visual improvement. Patients who received the REP1 gene therapy (timrepigene emparvovec (BIIB111) developed by Nightstar) did not have improved visual acuity (greater than 15 letters improvement) when compared to patients who did not receive the treatment. Biogen reported that they would be doing further data analysis before deciding what the next steps for this gene therapy would be.
4D MOLECULAR THERAPEUTICS CHOROIDEREMIA GENE THERAPY (4D-110) PHASE 1 CLINICAL TRIAL
There is also some uncertainty about the status of a choroideremia gene therapy (4D-110) trial developed by 4D Molecular Therapeutics (4DMT) and sponsored by Roche. This gene therapy treatment is delivered into the eye intravitreally and does not need to be injected under the retina. This means that the procedure should be easier to carry out than subretinal gene therapies like the gene therapy Luxturna. However, according to reports from Roche, results from laboratory studies showed that the treatment was not getting delivered to enough cells in the retina. Based on this, Roche has announced that they will not support any further development of this gene therapy treatment. 4DMT has stated that they believe early results from the Phase 1 clinical trial are promising and they intend to continue collecting data from this study even though Roche has stepped away from the project.
In addition to the trials mentioned above there are two active choroideremia gene therapy clinical trials: a Phase 2 trial (led by University of Oxford) and a Phase 1 trial (sponsored by Spark Therapeutics).
NANOSCOPE THERAPEUTICS INC PHASE 1/2A OPTOGENETICS CLINICAL TRIAL FOR RP
Nanoscope Therapeutics Inc, reported results from a Phase 1/2a optogenetics clinical trial for patients with retinitis pigmentosa (RP). Optogenetics uses gene therapy to turn non-light sensing retinal cells into light sensors. While this trial was specifically for individuals with RP, if successful, this treatment could be a treatment option for many different types of retinal degeneration.
In our June research news section (below), we highlighted results from another optogenetic study sponsored by GenSight. In this new study, sponsored by Nanoscope, gene therapy was used to deliver a gene called multi-characteristic opsin (MCO) to retinal cells of patients with advanced RP. What is unique about the MCO treatment is that it doesn’t require special goggles or retinal implants to work.
The MCO treatment was shown to be safe and all eleven treated individuals had improved functional vision as measured by shape discrimination and mobility tests. Patients also reported improvements in being able to perform daily activities. Nanoscope will be launching a late-stage Phase 2b clinical trial summer 2021.
HIGH LEVELS OF CAFFEINE MAY INCREASE THE RISK OF GLAUCOMA FOR THOSE AT HIGH RISK.
A new study suggests that consuming large amounts of caffeine may increase the risk of glaucoma for individuals with high genetic predisposition towards higher eye pressure. This new study led by researchers at Mount Sinai in New York was published in the journal Ophthalmology. Glaucoma is caused by high eye pressure. If left untreated, the high pressure can damage the optic nerve, which sends light signals to the brain, leading to vision loss.
In this study, researchers used data from a large databased called the UK Biobank, and analysed records from over 120,000 participants. These records included DNA (genetic data) questionnaires about life-style, including caffeine intake and eye health records. Using this information, researchers found that for most people, higher caffeine intake did not lead to an increased risk of glaucoma. However, for individuals with the strongest genetic risk for developing higher intraocular pressure, consuming three or more cups of coffee a day increased the risk of developing glaucoma.
It should be noted that this increased risk was only seen in individuals with high genetic risk and at high levels of caffeine intake. But it suggests that people who are at high risk may want to moderate their caffeine intake.
OPTOGENETICS RESTORES SOME VISION TO MAN WITH ADVANCED RETINITIS PIGMENTOSA
Scientists have reported that a patient achieved partial recovery of sight in a Phase 1/2 optogenetics therapy clinical trial. The study sponsored by GenSight Biologics, was published in the journal Nature Medicine.
Photoreceptors are our light sensing cells. However, in advanced retinal degeneration photoreceptors die, meaning that an individual can no longer sense light signals or make images. Scientists are studying if they can turn other surviving retinal cells, such as retinal ganglion cells (RGC) into light sensors using a technique called optogenetics. In optogenetics a gene that produces a light sensitive protein is added to retinal cells such as RGCs. When a specific wavelength of light shines on the cell, the light sensitive protein changes shape and turns the cell on or off.
The treatment in this study (called GS030) uses gene therapy to introduce a gene for an algae protein called opsin into RGCs. The patient then wears image-capturing goggles that amplify light signals and turns them into amber light wavelengths which activate the algae opsin. This study presents results from a 58-year-old French man who before treatment could sense light but not distinguish shapes. Within a few months of treatment he was able to see the white stripes at a pedestrian crossing and find objects on a table. The visual gains were modest, he isn’t able to see colours or distinguish faces or letters. However, this is a big step for the field of optogenetics, and it offers hope that this may be a viable treatment option for individuals with advanced retinal degeneration.
This study only reported on a single patient, the full trial will have up to 15 participants. It will be important to see if safety and efficacy are seen in a larger number of individuals and we look forward to hearing more results from this trial in the coming years.
GENE THERAPY CLINICAL TRIAL UPDATES: ACHROMATOPSIA AND X-LINKED RETINITIS PIGMENTOSA (XLRP)
In the first trial, Biogen announced that they did not see a significant improvement in the vision of patients with XLRP after treatment with a gene replacement therapy. This was a Phase 2/3 study, and the primary outcome scientists were looking for was improvement in light sensitivity as measured by macular integrity assessment (MAIA) microperimetry, 12 months after treatment. While there was no significant difference in this main outcome, the treatment was safe and scientists saw some improvements in other vision measurements, such as visual acuity under low light conditions. While disappointing, researchers will be doing further data analysis to determine if there are ways to improve the clinical trial or therapy and if it is worthwhile to continue testing this therapy.
The second study, by the University of Tübingen, published in the British Journal of Ophthalmology, reports on results from a Phase 1/2 gene replacement therapy trial for achromatopsia caused by mutations in CNGA3. The main purpose of Phase 1/2 trials are to make sure that a treatment is safe before testing it out on a larger group of individuals. Promisingly the CNGA3 gene therapy didn’t result in any serious side effects. However, there were no strong indications that the therapy improved vision. While there were functional benefits seen in a few tests, most of the vision tests did not show any significant improvement for treated patients. This trial was very small, having only nine participants, making it hard to draw a conclusion on if the treatment is likely to work. Researchers will be looking closely at the results from this study to help them develop a better clinical trial design for further trials and understand if the treatment might be more successful in younger patients with less vision loss.
CELL REPLACEMENT THERAPIES: THE SLOW MARCH FORWARD
Cell replacement therapies have the potential to reverse sight loss by replacing dead cells with healthy ones. In the last 10 years, research showed that transplanting stem cell derived photoreceptors could improve visual function in animal models of retinal degeneration. This provided hope that cell replacement therapy could be a treatment for advanced eye disease like age-related macular degeneration or inherited retinal diseases.
However, in the last few years some of the excitement has been tempered as scientists discovered that the improvement was not caused by the new photoreceptor cells transplanting, forming connections and transmitting light signals. In fact, many of the new cells did not functionally transplant into the retina. Instead, they temporarily released light-sensing molecules that were taken up by existing photoreceptors, a process called material transfer. This allowed the “old” photoreceptors to “reactivate” and work better than they did before. So, while vision may improve this would only be a temporary fix. Over time the re-activated photoreceptors are likely to stop working and continue to die.
Scientists are now putting renewed focus on identifying better ways to transplant new photoreceptors into the retina and importantly are testing for functional connections between the new photoreceptors and other cells in the retina. It’s crucial that these connections are established so that light signals can pass from the retina to the brain where images are formed.
In a new study published in the journal Cell Reports, Dr. Robin Ali (University College London) and his collaborators show that they are able to transplant stem cell-derived cone photoreceptors into the retina and that these cells make connections with other retinal cells, leading to improved visual function in a mouse model of retinitis pigmentosa. This is one of if not the first study to show a light response from transplanted cone photoreceptors, which are responsible for detail and central vision. Previous studies have focused on rod photoreceptors which are responsible for peripheral and low light vision. One of the factors that made this study successful appears to be that larger number of cells were transplanted. The researchers believe that this larger number is important to create a supportive environment and allow the new photoreceptors to integrate and develop after transplantation. Importantly, the researchers put a lot of energy into confirming if functional connections are being formed between the new photoreceptors and other retinal cells important for light transmission, as well as ruling out alternative explanations for improved visual responses like material transfer.
In many ways this is the story of science: two steps forward, one step back, a few more steps forward. This paper provides promising data that the field is continuing to move forward, learning from previous studies and slowly but surely getting closer to a potential stem cell therapy for advanced retinal degeneration.
IS EARLIER TREATMENT ALWAYS BETTER? THE CASE FOR ACTIVE MONITORING AND DELAYED TREATMENT
We often talk about the importance of early diagnosis and regular treatment to prevent progression of eye diseases like glaucoma and diabetic retinopathy. How about treatment as prophylaxis to prevent vision loss for individuals who are at risk of developing but don’t yet have an active disease? Two studies published in the journal JAMA Ophthalmology suggest that early treatment may delay the start of disease or slow progression but does not significantly improve vision loss which is one of the key outcomes you look for in a treatment.
In the first study, Dr. Michael Kass (Washington University), examined long term data from a landmark 2002 clinical trial. This study established that eye drops were effective at lowering eye pressure and reducing progression to primary open-angle glaucoma in patients who had elevated eye pressure but did not yet have glaucoma. However, looking at outcomes 20 years later researchers made the surprising discovery that overall, only 25% of individuals had vision loss from glaucoma, lower than expected. In addition, patients who had received early eye drops only had a slightly lower risk of vision loss than patients in the control group who didn’t receive drops until 7 years into the study. Based on this data, Dr. Kass suggests that doctors should discuss personal risk factors with their patients. Patients with elevated eye pressure but at lower risk of developing glaucoma may be able to delay starting drops as long as they are receiving regular and frequent monitoring so that treatment can start if glaucoma damage appears.
The second study presents two-year data from a trial looking at early anti-VEGF treatment for diabetic retinopathy (DR). In the early stages of DR, called non-proliferative DR, doctors can see changes in blood vessel growth in the retina, but there usually isn’t any impact on vision. If the vessels continue to grow this can lead to proliferative DR or diabetic macular edema (DME) where fluid leaks into the eye. Both proliferative DR or DME can cause vision loss and, if untreated, blindness.
This study divided patients with non-proliferative DR into two groups. The early treatment group received anti-VEGF injections. The second group, the control group, did not receive anti-VEGF injections unless their disease progressed, at which point they started treatment. Patients receiving early anti-VEGF developed less proliferative DR or DME compared to patients in the control group (14% vs 33%). Interestingly, despite this, after two years the amount of vision loss was essentially the same between the early treatment and control group. Researchers say it’s important to see if this trend continues after longer follow up (4 years). However, this data does suggest that if patients are closely monitored, treatment could be delayed until DR has progressed as early treatment does not appear to significantly improve vision.
In both of these studies, the researchers aren’t advocating for no treatment, but instead suggesting that individuals who are able to receive regular monitoring and are at lower risk of disease progression could delay the start of treatment until active disease begins. This approach should have limited impact on overall vision loss but may allow patients to delay some of the cost, time, and side effects that can accompany treatment.
PROMISING RESULTS FROM USH2A GENE THERAPY CLINICAL TRIAL
Biotechnology company, ProQR has announced promising results from their Phase 1/2 clinical trial for a new gene therapy for USH2A. This trial, which has a site in Montreal led by FBC-funded clinician-scientist Dr. Rob Koenekoop, is testing an RNA therapy, called QR-421, for Usher syndrome and non-syndromic retinitis pigmentosa caused by mutations in the USH2A gene. This therapy is specifically for individuals with mutations in a particular part of the USH2A gene (exon 13), which account for over 30% of USH2A cases.
QR-421 works in a different way than gene-replacement therapies (like Luxturna, the first gene therapy approved for an inherited retinal disease) where a new functional gene is put into cells to replace a mutated and non-functional gene. Instead, QR-421 uses a technique called RNA editing to fix mutations, in way that can be compared to a spell-checker function on a computer. QR-421 is a non-permanent treatment, meaning that patients will have to receive multiple treatments to maintain any benefit.
The Phase 1/2 clinical trial had 14 participants who each received one injection of the treatment. The trial showed that the treatment was safe and all participants showed a benefit, losing less vision in their treated eye than in their untreated eye. Based on these positive results, ProQR is winding down this early trial and hopes to launch larger Phase 2/3 clinical trials to gather more data about the effectiveness of this treatment in the near future.
MOVING A NEW TREATMENT FOR DIABETIC MACULAR EDEMA AND AGE-RELATED MACULAR DEGENERATION FROM THE LAB TO CLINICAL TRIALS
A new potential treatment for diabetic macular edema and age-related macular degeneration has been discovered by Canadian scientist Dr. Przemyslaw (Mike) Sapieha (Université de Montréal).
Many eye diseases, including diabetic retinopathy and wet age-related macular degeneration are caused by uncontrolled blood vessel growth behind the retina which if untreated can lead to bleeding and loss of sight. The primary treatment for these diseases is anti-VEGF injections which stop the growth of blood vessels. One of the problems with this type of treatment is that all blood vessel growth is stopped; both abnormal blood vessels and sometimes healthy blood vessels which are needed to keep the eye healthy and protect vision.
In this new study published in the prestigious journal Cell Metabolism, Dr. Sapieha’s team identified a way to distinguish between healthy and diseased blood vessels. They identified a molecule, BCL-xL, that is higher in abnormal blood vessels compared to healthy vessels. Dr. Sapieha then teamed up with a company, UNITY Biotechnology, who have developed drugs that block BCL-xL function. One of these drugs slowed the growth of abnormal vessels in a mouse model of retinal degeneration while allowing healthy blood vessels to survive.
This class of drugs is now being tested in a Phase I clinical trial to see if it is safe in individuals with diabetic macular edema or wet age-related macular degeneration. This is an exciting example of how innovative vision research can lead to new treatments.
NEW USES FOR OLD DRUGS: HOW CHOLESTEROL, DIABETES, AND HIV DRUGS MAY OFFER NEW WAYS TO TREAT RETINAL DEGENERATION AND AMD
CHOLESTEROL LOWERING STATIN DRUG MAY PROMOTE NEURON REGENERATION
FBC funded researcher Dr. Philippe Monnier has published a study in the journal Neurobiology of Disease that shows that cholesterol inhibition increases neuron regeneration and survival. The team used two approaches; the drug lovastatin and a genetic editing approach to lower cholesterol levels in an animal model of optic nerve damage. The optic nerve is made up of many cells that send signals from the light sensing photoreceptors to the brain. In these experiments, cholesterol lowering treatments increased optic nerve regrowth after injury. Researchers also saw that lowering cholesterol in the eye increased survival of both optic nerve cells and photoreceptor cells. Interestingly, previous studies have not shown such strong effects of cholesterol inhibition on neuron regeneration. More experiments will be important to understand what conditions promoted this effect in this study.
Unfortunately, this doesn’t mean that individuals with retinal degeneration should start taking statins! One important thing to note is that the drug treatment was given by intravitreal injections to the eye, meaning that a very concentrated dose of lovastatin was being given to a small region of the eye. There is no data to suggest that individuals who take cholesterol-lowering drugs have better vision or less retinal degeneration. However, this does suggest that there might be a new use for a currently existing and tested drug, and future work from Dr. Monnier’s team will explore this possibility.
HIV AND DIABETES DRUGS MAY LOWER THE RISK OF DEVELOPING AMD
Two research groups have used data from American health insurance claims to see if individuals on specific drugs have a lower risk of developing age-related macular degeneration (AMD).
In the first study, researchers studied claims from over 600,000 individuals, half of whom had a diagnosis of AMD. The study published in JAMA Ophthalmology found that individuals who had previously taken metformin, used as a treatment for type 2 diabetes and polycystic ovary syndrome, had a reduced chance of developing AMD. Interestingly, the effect was dose-dependent, and individuals on lower doses of metformin had the greatest benefit.
In the second study published in the journal Proceedings of the National Academy of Sciences, researchers found that build-up of a certain type of DNA (called Alu DNA) could kill retinal pigment epithelial cells in the retina, potentially contributing to macular degeneration. Based on this finding, they searched through claims from millions of patients to see if any drugs that block Alu DNA build up were associated with reduced vision loss. Indeed, they found that individuals who had taken a type of HIV drug known as nucleoside reverse transcriptase inhibitors (NRTIs) had less risk of developing dry AMD.
This data on its own isn’t enough to suggest that doctors should start prescribing these drugs, but they do provide interesting evidence that these drugs, or in the case of NRTIs, safer alternatives, could be considered for testing in new clinical trials to see if they help prevent AMD.
CLINICAL TRIAL UPDATE
This month we have clinical trial updates for gene therapy treatments for achromatopsia and a new anti-VEGF treatment for age-related macular degeneration (AMD).
ACHROMATOPSIA CLINICAL TRIAL UPDATES
Achromatopsia is an inherited retinal disease, where individuals have partial or total loss of colour vision as well as other vision problems, including increased sensitivity to light (including daytime blindness when there’s bright light), nystagmus, and lower visual acuity. Achromatopsia is caused by mutations in one of at least five different genes. There are a number of clinical trials testing gene therapy approaches for individuals with mutations in the most commonly affected genes, CNGA3 and CNGB3, and we have an update on two of these trials.
AGTC has provided an update on Phase 1/2 trials they are sponsoring, which are testing the safety and best dosage of the CNGA3 and CNGB3 gene therapies. The data was collected 3-12 months after treatment. 7 out of 26 (27%) of patients who received the CNGB3 gene therapy, and 3 out of 18 patients (17%) who received the CNGA3 gene therapy had some improvements in visual sensitivity. In both trials, all the patients who showed vision improvements had received higher doses of the gene therapy. There were no serious side effects reported in either of the trials. The trials will continue to enroll more patients and follow them for up to 12 months after treatment. They are also enrolling younger patients (as young as 4 years old) with the hope that the gene therapy might be successful at early stages of disease progression. AGTC will continue to report the results on this early stage trial over 2021 and 2022.
AMD CLINICAL TRIAL UPDATE
Roche has released the results of a Phase 3 trial of a next-generation anti-VEGF treatment, faricimab, for wet age-related macular degeneration (wet AMD). Anti-VEGF treatments work by blocking the VEGF molecule which promotes uncontrolled blood vessel growth in diseases like diabetic macular edema (DME) and wet age-related macular degeneration (wet AMD).
Faricimab is different because in addition to blocking VEGF, it also blocks a molecule called angiopoetin-2 (Ang-2) which also promotes blood vessel growth. There is hope is that this new treatment might be more potent than traditional anti-VEGFs because it’s attacking the problem (blood vessel growth) in two different ways. In brief, this trial showed that faricimab was as effective as another anti-VEGF (aflibercept (Eylea®)) treatment in maintaining or improving vision for patients newly diagnosed with wet AMD. 45% of patients taking faricimab were able to wait 16 weeks in between injections. This suggests that some patients diagnosed with wet AMD may have an new treatment option that could reduce how frequently they need to get anti-VEGF injections. Importantly, there were no unexpected negative side effects. Based on the strength of this data, Roche will be submitting faricimab for approval starting with the FDA in the U.S.
LHON STUDY FINDS DOUBLE THE IMPACT
In a surprising finding, scientists have shown that injecting a gene therapy for Leber’s Hereditary Optic Neuropathy (LHON) into one eye can improve the vision in a patient’s other eye.LHON is a genetic eye disease which leads to degeneration of the optic nerve, which transmits light signals to the brain. This can lead to sudden irreversible central vision loss.
In this Phase 3 LHON clinical trial, sponsored by GenSight Biologics and published in the journal Science Translational Medicine, scientists injected a gene therapy into one eye of an individual who was recently diagnosed (less than 12 months ago) with LHON. The eye that didn’t receive the gene therapy injection acted as a “control” to ensure that any vision changes or safety issues that occurred were caused by the treatment itself and not by something else. Interestingly (and unexpectedly) 78% of the 37 treated patients experienced improved vision not only in the treated eye but in both eyes.
Further research showed that the gene therapy was likely being transferred to the other eye, but importantly was not going to other parts of the body. These are exciting results and the researchers are completing a few more studies. The hope is that if these studies show that the gene therapy is consistently safe and effective, it could be a new treatment for LHON helping to preserve and even restore vision.
CLINICAL TRIAL UPDATES: GENE THERAPY FOR LCA10 AND A NEW TREATMENT FOR DM
Starting the new year with some updates on ongoing clinical trials! The biotechnology company ProQR announced that they had completed enrollment for a Phase 2/3 clinical trial of a gene editing approach for Leber congenital amaurosis 10 (LCA10). LCA10 is the most common and one of the most severe forms of the inherited retinal disease caused by mutations in CEP290. Currently, there aren’t any treatments for individuals with LCA10. The trial, using an RNA therapy called sepofarsen, is a potential treatment for individuals who have a specific mutation (pCys998X) in the CEP290 gene. It is encouraging that despite slow downs caused by COVID-19, the trial has completed patient recruitment and we are looking forward to hearing results from this study, expected in 2022.
The second update is from Roche on the Phase 3 trial of a next-generation anti-VEGF treatment, faricimab, for diabetic macular edema (DME). Anti-VEGF treatments work by blocking the VEGF molecule which promotes uncontrolled blood vessel growth in diseases like DME and wet age-related macular degeneration (wet AMD). Faricimab works a little bit differently, because in addition to blocking VEGF it also blocks a molecule called angiopoetin-2 (Ang-2). Ang-2 can also promote blood vessel growth and the hope is that this new treatment might be more effective than traditional anti-VEGFs because it’s trying to attack the problem (blood vessel growth) in two different ways.
Early results from the trial show that faricimab appears to be safe. In addition, more than half the patients treated were able to extend time between injections to 16 weeks which hopefully means less appointments and less injections. In addition to this trial, faricimab is also being tested in clinical trials for the treatment of wet AMD.
ANTI-VEGF BIOSIMILAR FOR TREATMENT OF WET AMD IS SAFE AND EFFECTIVE
Injections of anti-VEGF are the main treatment for wet age related macular degeneration (wet AMD). They help prevent blood vessel growth, fluid leaking into the eye, and play an important role in reducing or preventing vision loss. Anti-VEGF treatments are a type of medicine called biologics. This means the medicine is made at least in part in a biological source, such as in a cell. This is different to other drugs which are manufactured chemically.
Recently, as patents on anti-VEGF medicines are expiring, biosimilars which can be described as generic versions of a biologic, are starting to be developed.
Similar to generic drugs, biosimilars are usually less expensive than the brand name biologic and they are only available once a patent on a brand name treatment has expired. However, while the active ingredient in a generic drug is identical to the brand name drug, a biosimilar is very similar, but not exactly the same, as the brand name biologic. Because a biosimilar isn’t identical, additional research and clinical trials are important to make sure that the biosimilar is as safe and effective as the original biologic treatment.
A new study in the journal JAMA Ophthalmology has shown that SB11, a biosimilar of the anti-VEGF treatment ranibizumab (Lucentis®), has similar effectiveness and safety as ranibizumab.
This study was a phase III trial that took place in 9 countries and involved 705 patients with wet AMD who had never received anti-VEGF treatments before. The patients were randomly divided into two groups with one group receiving ranibizumab and the other group getting the ranibizumab biosimilar SB11. After 6 months patients in both groups had similar improvements in their vision and importantly, the biosimilar did not have any more or worse side effects than ranibizumab. While it will be important to see if the biosimilar continues to be as safe and effective as the original treatment after longer term follow up, this is a promising result.
You may hear more about biosimilars, not only for wet AMD but for other diseases in the next few years. Biosimilars hold the promise of being more cost-effective, which we can all agree is important. However, we also know that safety and effectiveness can’t be compromised and studies like this are crucial to ensure that. As both new brand name medicines and biosimilars for wet AMD become available, we encourage you to discuss this with your eye care provider so that you know more about the treatment you are taking, as well as other available options.
USING A GENE THERAPY APPROACH TO REGENERATE DAMAGED OPTIC NERVES
Scientists from the University of Cambridge have used gene therapy to regenerate damaged optic nerves in the eyes of mice, offering hope that this information could help in the development of new treatments for glaucoma.
The optic nerve carries light signals from the eye to the brain where images are formed. In diseases like glaucoma where the optic nerve is damaged, light signals can’t be passed on, leading to vision loss. The optic nerve isn’t normally able to heal once it is damaged, however research in the last few years has shown that it may be possible to stimulate nerves to regenerate.
In this study published in the journal Nature Communications, scientists used a gene therapy approach to get nerve cells to make higher amounts of a protein called Protrudin. What they saw was that after optic nerve damage, nerve cells that were making more Protrudin were able to regrow the nerve, while cells without gene therapy didn’t regenerate.
While this research is still a long way from being a treatment, it is one more step in the long search for a way to regenerate nerve cells for diseases like glaucoma or for spinal cord injuries.
AN OPTOGENETIC TREATMENTS TO RESTORE VISION
A study published in the journal Gene Therapy shows that a new light-sensing protein called MCO1 can restore some vision in blind mice using gene therapy.
MCO1 is a type of protein called an opsin that can detect light and pass on light signals. Opsins are normally found in light sensing photoreceptor cells which are lost in diseases such as retinitis pigmentosa and age related macular degeneration. Scientists are testing if opsins can be put into other surviving retinal cells to turn them into light sensors that replace damaged photoreceptors. This approach is called optogenetics and it could open the door to treatments that restore sight for individuals who have advanced retinal degeneration and don’t have many photoreceptors left.
In this study, a new more sensitive opsin, MCO1, was put in bipolar cells (a type of retinal cell) in the retinas of mice that couldn’t sense light, using gene therapy. The scientists found that mice who received the gene therapy regained some visual function and could navigate a maze faster and sense motion. This study was completed by the company, Nanoscope Technologies LLC. They are planning to start early phase clinical trials in humans later this year to test the safety of this potential treatment.
CRISPR: MAKING THE CUT TO RESTORE VISION. A NOBEL (PRIZE) ENDEAVOR
CRISPR (also known as CRISPR-Cas9) is a gene editing technique that allows scientists to cut DNA very precisely. It’s like a pair of molecular scissors that can be used to cut mutations out, or add new pieces of DNA into a gene. The importance of this tool was highlighted last month when Dr. Emmanuelle Charpentier (Max Planck, Berlin) and Dr. Jennifer Doudna (University of California, Berkeley) were awarded the 2020 Nobel prize in Chemistry for this discovery.
CRISPR is actually a natural part of a bacteria’s immune system. It was discovered by Dr. Charpentier in 2011 and soon after, working with Dr. Doudna, showed that it could be used to cut any piece of DNA very precisely and at specific sites. It’s been less than 10 years since its discovery but CRISPR has already had a huge impact on biomedical science and is the basis of new treatments being developed and tested in clinical trials for many diseases including cancer and blinding eye diseases. For example, a CRISPR-based treatment is being tested in a clinical trial for Leber congenital amaurosis and there are other potential treatments in development for inherited retinal diseases and other eye diseases such as glaucoma as the study below explains.
USING CRISPR TO REDUCE EYE PRESSURE CAUSED BY GLAUCOMA
Glaucoma is a chronic disease that occurs when increased pressure in the eye damages the optic nerve. The optic nerve sends light signals to the brain and when it is damaged it can lead to vision loss or even blindness. The first treatment option for open angle glaucoma, the most common kind of glaucoma, is usually pressure lowering eye drops. If this doesn’t work, surgery may be necessary. Researchers from the University of Bristol that are looking for a more long-term solution have turned to gene therapy.
Published in the journal Molecular Therapy the study used a CRISPR gene editing approach to block the function of a gene called Aquaporin 1, which transports fluid in the eye. By turning Aquaporin-1 off in the eyes of mice, researchers saw that eye pressure dropped and that the optic nerve had less damage compared to untreated mice. Follow up experiments are needed to understand if this treatment is safe and has long term effectiveness before it can be considered for a clinical trial. This study does show it may be possible to develop long term treatment options for glaucoma.
A NEW PATH TO NEURON REGENERATION
The death of neurons, such as retina cells, is responsible for many eye diseases, including inherited retinal diseases like retinitis pigmentosa, age related macular degeneration, and glaucoma. In humans, once a neuron or retina cell has died it can’t be replaced. However, this isn’t the case in all animals and a team of researchers in the United States, including FBC Scientific Advisory Board member Seth Blackshaw, has set out to understand how some animals regenerate their neurons.
The study, published in the prestigious journal Science, compared which genes were turned on after retina damage in animals that can regenerate their neurons (zebrafish) and in animals that can’t (mice). What they found was that after damage, reprogramming genes switch on in a type of neuron cell called a Müller glia cell. This turns Müller glia cells into a progenitor or stem cell that can make new neuron cells that help fix the damaged retina. In comparison, in mice, these reprogramming genes are blocked from switching on, meaning that Müller glia cells don’t become progenitor cells. When scientists partially removed this blockade, mice were able to make some new neuron cells.
This study shows that it may be possible to regenerate some neurons in the eye. Scientists will now try to identify how they can completely and accurately turn off the reprogramming blockade to promote regeneration. Excitingly, this research may also be useful to researchers studying other diseases caused by neuron cell death, including neurodegenerative diseases like Parkinson’s disease.
SOLVING A STEM CELL MYSTERY AND DRIVING THE DEVELOPMENT OF CONE PHOTORECEPTOR CELLS
A new study by FBC-funded researcher Dr. Michel Cayouette (Institut de recherches cliniques de Montréal), has identified two molecules (Pou2f1 and Pou2f2) that drive stem cells to make cone photoreceptor cells. Cone photoreceptor cells are the light sensing cells responsible for detail and central vision and they are lost in eye diseases like age-related macular degeneration, and advanced inherited retinal diseases like retinitis pigmentosa.
Stem cells have the ability to make many new types of cells and are being considered as treatments for blinding eye diseases, replacing cells that have been lost or damaged. A large challenge is that while stem cells like retinal progenitor cells (RPCs) can make different retinal cells (i.e. photoreceptors, retinal ganglion cells, muller glial cells), it isn’t clear how RPCs decide which cells to make or if this process can be controlled to create the specific cells that are needed for treatment.
Published in the journal Development, Dr. Cayouette’s research sheds light on this process, showing that Pou2f1 and Pou2f2 are turned on when RPCs are making cone cells, and are turned off when RPCs aren’t making them. The study also shows that turning on Pou2f1 and 2 artificially drives RPCs to make more cone cells, and that RPCs don’t make as many cone cells if Pou2f1 and 2 are turned off too soon. Dr. Cayouette and his team are now studying if this information can be used in regenerative medicine. For instance, if Pou2f1 and 2 are turned on in a non-stem cell, like a retinal ganglion cell, will it start behaving like a cone photoreceptor? This exciting discovery is giving scientists the information and inspiration they need as they develop stem cell therapies.
Learn more about the research and the scientists behind it in this interview with Dr. Cayouette and his PhD student Awais Javed.
NEW AND EMERGING: CLINICAL TRIAL UPDATES FOR GEOGRAPHIC ATROPHY AND GLAUCOMA
GEOGRAPHIC ATROPHY TRIAL
A news release from Apellis Pharmaceuticals announced the results of a clinical trial testing the drug pegcetacoplan as a treatment for geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD). GA can lead to blindness and there are currently no approved treatments for it. This Phase 2 study conducted in the United States, Australia, and New Zealand was randomized, and participants received either intravitreal injections of pegcetacoplan or a placebo. The study showed a 39% reduction in GA disease progression and Apellis has recently announced completion of enrollment of a larger Phase 3 clinical trial of pegcetacoplan with early results expected in 2021.
Glaucoma, one of the leading causes of blindness in Canada, is caused by damage to the optic nerve, which sends light signals to the brain. While there is no cure for glaucoma, most patients can avoid blindness by using eye drops to lower the high eye pressure that is responsible for the damage. On top of the challenge of taking frequent eye drops, the medicine has a number of side effects including pain, headaches and blood pressure changes. A new clinical trial, launching soon will test if a treatment called selective laser trabeculoplasty (SLT) could be a better alternative. SLT is a low-energy laser procedure that would be performed once a year and could replace daily eye drops. The clinical trial, called “Clarifying the Optimal Application of SLT” or COAST will be conducted by West Virginia University and University of Pittsburgh, with plans to enroll over 600 patients.
SPICE UP YOUR LIFE? TURMERIC AS A TREATMENT FOR UVEITIS.
Researchers at Texas A&M University have produced a new treatment from the spice turmeric. This treatment may reduce inflammation from uveitis – a common condition often occurring after infection, cancer or autoimmune diseases that can lead to pain and vision loss.
The uveitis centered study, led by Dr. Erin Scott and published in the journal Science Advances tested a new form of turmeric designed to increase absorption and found that it was safe and reduced uveitis. Drug delivery is a challenge with any oral medicine, because it has to pass through the intestines, get absorbed into the circulatory system before being delivered to the tissue in need. Drug delivery to the eye is even more challenging because of the blood-ocular barrier – a physical barrier that tightly controls what substances can enter the eye.
Dr. Scott and her colleagues designed a new formulation of curcumin (one of the components of turmeric) that included nanoparticles. These nanoparticles were able to interact with molecules on the blood-ocular barrier and allow the curcumin to pass through into the eye. Curcumin is very attractive as a potential drug because it has no known negative side effects unlike current treatments for uveitis. The next step for this treatment is to test it out in a clinical trial (in dogs!) and based on these results, Dr. Scott is hopeful that it could also be considered as a treatment for humans.
IDENTIFYING NEW GENETIC CAUSES OF INHERITED RETINAL DISEASE
FBC-funded clinician-scientist Dr. Elise Héon has discovered a new genetic cause for non-syndromic inherited retinal diseases (IRDs). With advances in genetic sequencing, we now know of over 250 genes that cause IRDs. However, over 30% of patients still get a negative result after genetic testing which means that their mutation is not one of these known genes. Clearly there is still much more to learn and many more genes to identify. This is Dr. Héon’s specialty, deciphering the genetic causes of IRDs.
In this study, Dr. Héon and her international collaborators used in-depth genome sequencing and identified mutations in the DYNC2H1 gene in patients with non-syndromic IRD. The DYNC2H1 gene provides instructions to make a molecule called dynein-2, which acts like a motor, physically transporting cargo around the cell. This study by Dr. Héon’s team, published in the journal Genetics in Medicine, also showed that mutations in DYNC2H1 cause a large decrease in dynein-2’s motor function confirming that the mutations had a real impact on cell function. This study brings research one step closer to the goal of identifying and understanding all the genetic causes of IRDs, information that is crucial for accurate diagnosis and development of new treatments.
DOES YOUR SALIVA HOLD THE KEY TO REDUCING AMD?
In a recent study published in Scientific Reports, Dr. Jacob Rullo (Queen’s University) recipient of FBC’s Clinicial Scientist Emerging Leader award, has shown that patients with age-related macular degeneration (AMD) have different microbiomes compared to individuals without AMD, providing a link between inflammation and AMD progression.
AMD is the leading cause of vision loss in Canadians over the age of 50. There are many factors that can lead to the development and progression of AMD, including age, genetics, and environmental factors. In addition, there is evidence that inflammation may also play a role. Other inflammatory diseases such as Crohn’s disease, arthritis, and coronary artery disease have been linked to changes in gut and oral bacteria (also called the microbiome). These changes can increase local inflammation which may trigger inflammation in other parts of the body. Based on these observations, Dr. Rullo decided to study if changes in the microbiome might also be driving AMD development.
Comparing oral and nasal samples from individuals who had just been diagnosed with AMD to those who didn’t have AMD, Dr. Rullo and his colleagues found that there were different types of bacteria in the two groups. Some of the bacteria that were higher in individuals with AMD have been previously found in individuals with coronary artery disease. This research is intriguing but needs to be repeated with more patients and importantly, more research needs to be done to figure out if a treatment could shift the bacteria back to “normal” and slow down AMD development or progression.
Research developments like the ones shared above would not be possible without your support. Donate today to help advance vision research. To learn more about other FBC funded researchers, visit our FBC Funded Research page.
CAN OUR IMMUNE SYSTEM HELP REDUCE DIABETIC RETINOPATHY PROGRESSION?
Published in the prestigious journal Science, a study led by Dr. Przemyslaw (Mike) Sapieha (Hôpital Maisonneuve-Rosemont (CR-HMR)) has shed light on how disordered blood vessels can be cleared to make room for healthy vessels in diabetic retinopathy. This discovery could lead to the development of a treatment for this serious complication of diabetes.
Diabetic retinopathy is the leading cause of blindness among working-age adults and is caused by damage to the blood vessels at the back of the retina, the light sensing part of the eye, and growth of abnormal blood vessels that can leak fluid into the eye.
This study shows that in diabetic retinopathy, the body tries to put the brakes on the abnormal growth of blood vessels by encouraging the blood vessel cells to enter a non-growing state called senescence. Interestingly, using a mouse model, Dr. Sapieha’s team also found that the body may be able to use the immune system to clear these senescent blood vessels, creating room for new healthy blood vessels to grow. The researchers also discovered that similar immune reactions were also happening in the eyes of patients with diabetic retinopathy.
This suggests that the body might have the tools to slow down diabetic retinopathy. But we know that most individuals with advanced diabetic retinopathy require treatments to slow vision loss and that the abnormal blood vessels won’t clear up on their own. This leaves us with the intriguing possibility that if researchers can figure out a way to activate the body’s own defense mechanisms, this might be a new way to slow or stop the progression of diabetes related vision loss.
CLINICAL TRIAL UPDATES:
GENE THERAPY FOR X-LINKED RETINITIS PIGMENTOSA & LONG LASTING ANTI-VEGF TREATMENTS
This month we received updates on three clinical trials!
The first two trials were gene therapies for X-Linked Retinitis Pigmentosa (XLRP), characterized by progressive vision loss in boys, beginning with night blindness and often resulting in total vision loss. XLRP is caused by mutations in the RPGR gene which leads to death of light sensing photoreceptor cells in the retina. Both of the clinical trials discussed below are testing if putting a functional copy of the RPGR gene into retinal cells using gene therapy can prevent retinal cell degeneration and preserve vision.
MEIRAGTX AND JANSSEN PHASE 1/2 CLINICAL TRIAL UPDATE: XLRP
MeiraGTX and Janssen provided an update of their ongoing Phase1/2 clinical trial. In this study, 5 out of 7 patients had stable or improved vision up to 6 months after treatment. The main purposes of Phase 1/2 trials are to make sure the treatment is safe and to figure out the best dose. That’s why it was good to hear that the gene therapy didn’t have major negative side effects. Based on these promising (but early) results, this study will continue with the hope of starting a larger Phase 3 clinical trial soon.
AGTC PHASE 1/2 CLINICAL TRIAL UPDATE: XLRP
AGTC recently released data from an ongoing Phase 1/2 clinical trial to test safety and dose. Based on this study and looking at high dose that will be used in the next phase of the study, 4 of 6 patients responded to the treatment 6 months after receiving gene therapy. The company is expanding the Phase 1/2 clinical trial with plans to launch a Phase 2/3 trial in 2021. Updated September, 2020.
ROCHE PHASE 3 CLINICAL TRIAL UPDATE: WET AMD
Finally, we heard promising results from Roche about a clinical trial that is testing a small eye implant called a port delivery system (PDS). The PDS slowly releases an anti-VEGF (ranibizumab (Lucentis)) and may reduce the need for frequent injections for patients with wet AMD. In this Phase 3 trial, patients with wet AMD received either PDS filled with ranibizumab or regular ranibizumab injections. Patients who received PDS were able to go 6 months between medicine refills and had as good visual outcomes as patients who received monthly injections. PDS is also being tested for use in diabetic macular edema.
We know many of you are eagerly awaiting new treatments that are less invasive and less frequent and we look forward to telling you more about longer term results from these studies.
SMALL BUT MIGHTY: USING NANOPARTICLES TO CREATE ARTIFICIAL RETINAS
A new study published in the journal Nature Nanotechnology identifies a new potential way to restore vision in individuals with retinal degeneration, with a single injection of nanoparticles creating a working artificial retina and restoring vision in blind rodents.
Many forms of vision loss are caused by degeneration of light sensing cells in the retina, including inherited retinal diseases such as retinitis pigmentosa, age-related macular degeneration, and diabetic macular edema. While retinal protheses have been developed and tested, they often aren’t very sensitive, not producing clear images and requiring invasive surgery, wiring, and external devices like cameras.
Nanoparticles are extremely small particles that can be made of many different types of materials and are used in fields from manufacturing to fabric production and increasingly health and medicine. In this study a team of scientists from Italy, used nanoparticles to create a new kind of artificial retina. The team used nanoparticles attached to a type of semi-conductor material that can sense and pass on light signals. Nanoparticles were injected into the retinas of rats who had retinitis pigmentosa. The nanoparticles were able to “replace” damaged retinal cells by sensing and passing on light signals to other cells in the retina. Rats who received nanoparticle treatment demonstrated improved vision up to 8 months after the injections.
While there are still many steps before this can be tested in humans, this is an exciting example of innovative treatments that are in development and will hopefully be moving from the lab into the clinic in the coming years.
UNDERSTANDING GLAUCOMA: HOW STEM CELLS PROTECT THE OPTIC NERVE
Research from the University of Maryland has identified for the first time that stem cells live near the optic nerve – information which may shed light on how glaucoma develops. The optic nerve transfers light signals from the retina to the brain and when damage to the optic nerve occurs, this causes vision loss in diseases such as glaucoma. Until now scientists didn’t think that the optic nerve could heal if it was damaged. This study, published in the journal Proceedings of the National Academy of Sciences (PNAS), shows that in both humans and animal models, a type of stem cells lives close to the optic nerve and may protect the optic nerve from damage. These stem cells are present at birth and seem to decrease as people age. This could shed light on why optic nerve damage caused by glaucoma increases with age.
This information also opens the door to new treatments for glaucoma. For example, the research team is now trying to identify if the stem cells are secreting specific “protective” molecules which could potentially be used as a treatment for glaucoma or other eye diseases where the optic nerve is damaged.
THE EYES ARE THE WINDOW TO THE….BRAIN?
How the retina became a key model for brain research.
The BRAIN Initiative was launched by the National Institutes of Health (NIH), in the U.S to accelerate development of innovative technologies in order to treat neurological disorders such as Parkinson’s and Alzheimer’s disease, depression and autism. Over $1.3 billion (USD) has been awarded to researchers since 2014. Amazingly, about 40% of projects funded are vision related or involve vision health researchers. This is because when researchers want to learn about the brain they often start with the retina!
Just like the brain, the retina is made of neural tissue and is composed of different types of neurons (also called nerve cells). In addition, the retina and brain are attached via the optic nerve which transmits light signals to the brain to form images. The retina however is much more accessible and easier to study than the brain. While the neurons in the retina and brain aren’t exactly the same, studying how neurons in the retina process and transmit sensory information provides important information about how cells in the brain might function.
You can learn more about different types of experiments funded by the BRAIN initiative in an article published by the National Eye Institute (NEI), including work to identify different cell types in the brain and retina, online crowdsourcing games to map neural connections and development of visual prosthesis.
Last year, Fighting Blindness Canada (FBC) expanded our mandate to including all blinding eye diseases, knowing that advances in one disease drive innovation for vision research in general. It’s clear that this extends to other areas of research as well, including cancer, immunology and neurological or brain research. In fact many FBC funded researchers, including Dr. Phillippe Monnier and Dr. Elizabeth Simpson are also involved in research into brain function and disease in addition to their work on vision loss. It’s certainly inspiring to see how our vision researchers are not only helping to develop sight saving treatments but are helping scientists in other fields move forward!
CHOLESTEROL LOWERING STATIN DRUGS MAY PROTECT AGAINST DIABETIC RETINOPATHY
New study suggests statins use may reduce risk of diabetic retinopathy.
A meta-analysis study, published in the European Journal of Ophthalmology last month showed that individuals who took statins were less likely to develop diabetic retinopathy. Statins are drugs that are commonly used to lower cholesterol levels. Previous studies have indicated that patients who are taking statins have reduced rates of diabetic retinopathy and are less likely to need treatment including laser treatment, anti-VEGF injections and vitrectomies than patients who aren’t taking statins. This new study analysed data from six different publications to see if the results were consistent among the different studies, patient populations, and countries. And indeed, with a combined patient population of 558,177, these results were confirmed. This is very interesting but doesn’t mean that people should just start taking statins! Like any drug, statins can cause side effects so it will be important to learn more about how statins are impacting diabetic retinopathy. For example, researchers will need to understand if statins or lowered cholesterol are directly reducing diabetic retinopathy or if patients who are on statins are more likely to be making healthy lifestyle choices or have certain favorable healthcare characteristics which may lead to better outcomes.
NEW TREATMENT FOR AMD MAY REDUCE INJECTION FREQUENCY
A new anti-VEGF drug expands the AMD treatment arsenal.
The discovery of anti-VEGF drugs to treat neovascular age-related macular degeneration (also called wet AMD) was a game-changer and anti-VEGF injections are now the first line therapy for the majority of patients diagnosed with wet AMD. Despite this success, some people do not respond to current treatments and the frequency of injections can put a large burden on patients and their families. Scientists and pharmaceutical companies are trying to solve these problems and there are new treatments in development in the lab and in clinical trials.
One of these, brolucizumab (Beovu®, Novartis) is an anti-VEGF injection that was recently recommended for funding by CADTH (the Canadian agency that makes recommendations about the efficacy and cost effectiveness of new drugs). In clinical trials, brolucizumab given every 12 weeks, was shown to be as effective as another anti-VEGF drug (aflibercept – Eylea®, Bayer) given every 8 weeks. Currently, CADTH is recommending that brolucizumab should only be used for patients who have not yet started anti-VEGF treatments. The next step will be for the provinces to decide if they will fund brolucizumab through the public health system.
Based on input from the community, FBC submitted a patient response to help regulators understand the experience of individuals living with wet AMD and some of the challenges they face with current treatment. Access the full CADTH recommendation. Access the FBC patient group submission.
TWO NEW RESEARCH PROJECTS FROM FBC-FUNDED CLINICIAN SCIENTISTS: ORAL RETINOID THERAPY MAY IMPROVE VISION IN SOME PATIENTS WITH LATE-ONSET RETINITIS PIGMENTOSA (RP).
A new study published in the journal BMJ Open Ophthalmology, shows that a 7-day treatment with a synthetic retinoid replacement (9-cis-retinyl acetate) can lead to improvements in vision which lasts up to 6 months. FBC funded researcher Dr. Robert Koenekoop (McGill University) participated in this phase 1b clinical trial which took place in Montreal and Dublin, Ireland. Patients in this trial had a rare dominant-acting mutation D477G in the RPE65 gene which leads to vision loss, usually starting in adulthood. Because of how the mutation affects the gene, this mutation cannot be treated with a gene therapy approach which can be an option for many other individuals with RPE65 mutations.
RPE65 plays an important role in producing the compounds that photoreceptors need to sense and transmit light signals. When RPE65 is mutated, these important compounds are depleted in photoreceptor cells, meaning that light signals aren’t generated, leading to vision loss. This study shows that oral retinoid therapy may help replace some of these critical compounds and could be a potential therapeutic option for individuals with this dominant acting mutation.
While this is an exciting study, it is an early phase clinical trial designed primarily to test the safety of the new therapy. Further and larger clinical trials will be important to confirm if the therapy can consistently improve vision in a safe and effective way. We look forward to hearing more in the years to come!
NOVEL CHOROIDEREMIA MUTATION IDENTIFIED IN THE CHM GENE
Funded by FBC and published in the journal Opthalmic Genetics, Dr. Ian MacDonald (University of Alberta) has discovered a novel mutational event in the CHM gene leading to choroideremia. Choroideremia is an X-linked progressive inherited retinal disease that affects males. It is caused by a number of different mutations in a single gene, the CHM gene. There are currently no approved treatments for choroideremia, although a gene therapy is currently being tested in clinical trials.
As new treatments are being developed it is more important than ever for patients to have an accurate genetic diagnosis to find out if they are eligible for these gene-specific treatments. However, if the genetic mutation hasn’t been identified before, it may not be possible to get a genetic diagnosis, and in fact in some clinics up to 50% of patients are unable to get a genetic diagnosis. In this study, Dr. MacDonald and his team, using advanced genetic techniques, identified a previously unknown mutation event that causes choroideremia: the insertion of a “random” piece of DNA called a retrotransposon into the CHM gene, which stops the gene from working. This study is important to grow the panel of known gene mutations and increase the chance that an individual can get an accurate genetic diagnosis. Access article abstract.
THE PROMISE AND CHALLENGES OF INNOVATIVE TREATMENTS FOR INHERITED RETINAL DISEASE
This short article, from Dr. John Dowling (Harvard University) in the high impact journal Science, provides an interesting overview of different therapeutic approaches that are showing promise for inherited retinal diseases. Learn more about the promise and challenges of potential treatments such as stem cell therapy, gene therapy and retinal implant.
FINDING WAYS TO PREDICT PROGRESSION OF AGE-RELATED MACULAR DEGENERATION (AMD)
Two studies using artificial intelligence and patient reported outcomes are identifying ways to predict disease progression earlier. Learn more….
Age-related macular degeneration (AMD) is the leading cause of vision loss for Canadians over the age of 55. It occurs when the central portion of the retina, the light sensing tissue at the back of the eye, gets damaged. There are two types of AMD, dry AMD, which is more common and usually less severe and wet AMD which progresses from dry AMD and is the major cause of vision loss. It’s important to catch wet AMD as early as possible and to monitor progression closely so that it can be treated and slown down to prevent vision loss.
Two studies recently published are looking at the same question in very different ways: Can you predict when AMD will progress? The first study, published in the prestigious journal Nature Medicine, takes an artificial intelligence (AI) and deep learning approach. The UK-based team, a collaboration between scientists at the company DeepMind, University College London and Moorfields Eye Hospital, showed that a computer-based AI program was better than 5 out of 6 experts at predicting disease progression from OCT images. The second Australian study took a very different approach, investigating if there was a link between patient reported outcomes and AMD progression. The study found that patients who self-reported higher vision impairment were also at higher risk of developing wet AMD. Taken together these two studies are identifying new ways to detect AMD progression earlier and more accurately, with the aim of improving outcomes and reducing vision loss.
FBC FUNDED RESEARCHER FINDS LINK BETWEEN VITAMIN D AND RETINAL DISEASE.
FBC Clinician Scientist Emerging Leader, Dr. Jacob Rullo from Queen’s University, has published a paper showing levels of vitamin D are higher in the eyes of patients with retinal disease, such as age-related macular degeneration and diabetic macular edema. Previous work looking at blood levels of vitamin D was inconclusive. This study shows that vitamin D is present in the eye and that it may play a role in disease progression.
RESEARCHERS TURN SKIN CELLS INTO LIGHT-SENSING EYE CELLS
Researchers, from the University of North Texas Health Science Center have published a technique for reprogramming skin cells into light-sensing rod photoreceptors. This new technique allows researchers to skip a step in the process, and may provide a faster way to produce photoreceptors for cell replacement and stem cell therapy. When these reprogramed cells were transplanted into the eyes of blind mice, researchers detected some light under specific experimental conditions. However, this is only the first step and future experiments are required to see if the reprogrammed cells can actually restore long-term sight.
NEI RESEARCHERS LINK AGE-RELATED DNA MODIFICATIONS TO EYE DISEASE RISK
Findings point to targeting epigenome as a potential therapeutic strategy
Have you heard of the epigenome? The epigenome is all the chemical modifications or “marks” on our DNA which control which genes turn on and off. The epigenome can change in certain diseases like cancer, and now researchers at the National Eye Institute (USA) have published a study showing that it can change in the photoreceptor cells of mice as they age. Photoreceptors need energy to function and researchers found that as mice age, there were epigenetic changes that affected how their cells could use energy – demonstrating a clear link between aging, how cells use energy, and age-related eye diseases like age related macular degeneration (AMD). It might also point to a new therapeutic option: finding ways to change the epigenome to reduce vision loss.
This page is updated monthly. Visit this page next month for more exciting updates in vision research.
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