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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