Aug 14, 2019
The Era of Gene Therapy – A Panel Discussion
In this panel discussion from Vision Quest Vancouver on April 27, 2019, experts from around the world introduced the new era of gene therapy and discussed what this means for the future of blinding eye diseases and people living with vision loss. The panelists were: Dr. Catherine Tsilfidis, Senior Scientist, Ottawa Hospital Research Institute, Dr. Jane Green, OC, ONL, BSc, MSc, PhD, CCMG (hon), FCAHS, Honorary Research Professor, Discipline of Genetics, Faculty of Medicine, Memorial University, Dr. Kali Stasi, MD, PhD, Director Translational Medicine Ophthalmology, Novartis Institutes for BioMedical Research, Dr. Jean-Yves Deslandes, Chief Medical Officer, HORAMA, Jack McCormick, past co-chair of FBC’s National Young Leaders Program.
What is Gene Therapy?
A gene therapy is a new kind of treatment that works by delivering a functioning copy of a gene directly into a patient’s cells. This newly introduced, functioning gene acts as a treatment by replacing a mutated gene that is not working properly. After just a single treatment, gene therapy has the potential to provide lifelong benefits.
The goal of gene therapy is to replace a mutated gene with a new, functioning gene. A “transporter” is used to deliver the new gene. This gene transporter is called a vector and is made from an altered virus. To prepare the virus for this important transporting job, the viral genes are removed and the new functioning gene is inserted inside the virus. Vectors are carefully designed to transport genes into the specific cells where they are needed, such as the eye’s light-sensitive photoreceptor cells. Once the vector has delivered the gene, the eye will be able to make the proteins that are needed to support healthy cells, prevent further vision loss, and even restore vision!
Gene therapies are poised to transform healthcare by making personalized medicine possible. Although scientists are working on gene therapies for many different diseases, some of the most rapid growth in the field is in inherited retinal diseases.
Inherited retinal diseases, or IRDs, is the term used to describe a diverse, rare group of eye diseases. Each IRD is different, but they all share two common traits: 1) they result in progressive retinal degeneration that leads to severe visual impairment or blindness; and 2) they are “inherited,” which means that they are caused by one or more genetic mutations that are inherited from the DNA we receive from our parents. Today, more than 250 genetic mutations have been identified as causes for IRDs. Some of the IRDs that could be treated with gene therapy include retinitis pigmentosa (RP), Stargardt disease, choroideremia, Usher syndrome, X-linked retinoschisis (XLRS), achromatopsia (ACHM), and Leber congenital amaurosis (LCA).
How do we learn about the genetic component of inherited retinal diseases (IRDs)?
Before we could even think about gene therapy a lot of important work had to be done to gain a solid understanding of genetics, mutations and inherited retinal diseases. The structure of DNA was identified in 1953 but no one knew how to read the information encoded in the double helix. We knew that some conditions ran in families, but not what a normal gene sequence looked like – let alone what mutations looked like. The Human Genome Project took thirteen years (1990-2003) to sequence just one human genome, but this project led to the identification of many specific genes and disease-causing mutations.
Dr. Jane Green has been working at the forefront of genetic research in Canada since the 1960s, when she started her studies in genetics with Dr. David Suzuki. In the 1970s Dr. Green moved to Newfoundland where she played a critical role in mapping IRDs across the province.
Newfoundland is unique in that it happens to have a high population of people living with inherited retinal diseases. This is due, in large part, to the way the population was founded in the 1700s and 1800s: the ships that brought migrants over from England and Ireland landed in remote, coastal communities where their passengers could set down roots. To this day, many of the descendants of those founding populations remain in the area. When a population is established in this way, it often leads to a loss of genetic variation and an increase in genetic diseases.
In 1978, Dr. Green met an ophthalmologist named Dr. Gordon Johnson, who, in his St. John’s practice, saw many patients who were reporting eye diseases that ran in their family. In order to study those diseases, Dr. Green participated in weekly inherited disease clinics in St. John’s to gather more information. She then visited outposts at rural hospitals to meet affected families, in order to try and understand the clinical features of their diseases and to see if other people in the community were similarly affected. On these visits, she also collected any relevant family histories of disease by talking to multiple generations of the same families, including grandparents and great-grandparents. Some families were very large, which made it easier to recognize hereditary diseases. Crucially, this also gave Dr. Green the opportunity to educate families and health care providers about genetic diseases in the area.
Health care providers in these rural clinics saw many inherited retinal conditions, the two most common being Stargardt Disease and Bardet-Biedl Syndrome (BBS). Many families were affected by these diseases, and over time molecular studies were performed to identify these mutations.
One of the diseases that was of particular interest to Dr. Green was Newfoundland Rod-Cone Dystrophy (NFRCD). Dr. Green met a young boy in the 1980s whose disease was characterized by night blindness from birth and reduced central vision. In the 1980s and 1990s, Dr. Green identified 28 patients that shared this early retinal dystrophy. They were all from the Conception Bay area (100 miles from St. John’s) and all had a distinctive retinal appearance. Further research revealed that all 28 were distantly related.
By 2000, Dr. Green’s research had revealed that over 30 people within a ten-mile cluster had mutations on the RLBP1 gene – one of the genes that can cause retinitis pigmentosa. Within this group of individuals, Dr. Green identified three separate mutations affecting this gene, which was why it had taken so long to recognize that they were all affected by the same disease. There were also many clusters of families affected by retinitis pigmentosa around the province. To study this disease, Dr. Green participated in clinical studies that identified three known types of RP: dominant, recessive and x-linked, and one unknown type. Dr. Green and other researchers have followed these families for many years in order to identify specific genes and genetic mutations and, most importantly, to provide information back to those families and the community about the impact of their hereditary diseases.
People would often ask Dr. Green: “What can be done about my condition?” For the longest time, she was unable to provide any concrete medical answers. Fortunately, we are now at a point in time where there have been significant developments in gene therapy research, which means we are closer than ever to finding an answer.
What are some recent clinical developments in gene therapy?
Dr. Kali Stasi is a clinician-scientist who works in clinical development for the pharmaceutical company Novartis. Her job is to translate gene therapy and cell therapy research into clinical trials, and ultimately into new treatments with the potential to impact people living with inherited retinal diseases.
Dr. Stasi is currently studying the RLBP1 mutation associated with retinitis pigmentosa (RP) – the very same gene that Dr. Green began studying in the 1980s. Mutations in the RLBP1 gene cause a form of RP that currently has no treatment. This disease is characterized by early, severe night blindness and slow dark adaptation from childhood, followed by progressive loss of visual acuity and field. Most people affected by mutations in the RLBP1 gene are legally blind by middle adulthood.
With her team at Novartis, Dr Stasi selected this disease as a promising candidate for gene therapy. Her team’s first step was to conduct a natural history study to understand how the disease progresses “naturally,” which means without any treatment. Many of Dr. Green’s patients were involved in the natural history study. Next, Dr. Stasi helped to design and initiate a Phase I/II trial for an RLBP1 gene therapy, which delivers a functioning copy of the RLBP1 gene to trial participants who have retinitis pigmentosa that is caused by mutations to the RLBP1 gene.
At Novartis, Dr. Stasi is also involved with a gene therapy called Luxturna, which is the first FDA-approved gene therapy for a genetic disease.
Luxturna is approved to treat people who have an inherited retinal disease that is caused by “biallelic” RPE65 mutations. “Biallelic” means that there are mutations in both copies of the gene: as a result, some people with this “genetic diagnosis” are diagnosed with Leber congenital amaurosis (LCA), while others might have received a diagnosis of retinitis pigmentosa (RP). Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina, thereby stopping further vision loss and restoring some functional vision.
Luxturna was developed by Spark Therapeutics, but in January 2018 they entered into an agreement that allows Novartis to supply the gene therapy outside of the United States. Luxturna received FDA approval in the U.S. in December 2017, and received European EMA approval in November 2018. Novartis is committed to ensuring that patients outside the U.S. will have access to this innovative gene therapy treatment and is actively engaging with medical experts, health authorities and reimbursement agencies in multiple countries, including Canada, to make it so.
Jack McCormick, one of the past co-chairs of FBC’s National Young Leaders Program, is living with Leber Congenital Amaurosis (LCA) caused by mutations in his RPE65 genes, which is the specific genetic disease that Luxturna was designed to treat. Jack was diagnosed at the age of two with cone-rod dystrophy. The doctor told his family that his vision would be stable, but impaired; however, in his teenage years Jack noticed his eyesight was further deteriorating, and when he revisited an ophthalmologist he was diagnosed with LCA. Jack has witnessed huge changes in the field of ocular genetics in his 22 years. He is excited by the prospect of Luxturna, but notes that it is not yet available in Canada. We need to bring our voices together to push the needle forward!
Dr. Catherine Tsilfidis has worked for 20 years in the fields of vision science and gene therapy. She is currently working with a gene called XIAP (x-linked inhibitor apoptosis protein), which can block cell death. Dr. Tsilfidis is particularly interested in working with this gene because a spectrum of retinal diseases are caused by this type of cell death. She hypothesizes that if we are able to use XIAP gene therapy to block cell death in the eye, we can use it to target many different kinds of retinal diseases. Her team has looked at XIAP gene therapy in relation to many diseases, including retinitis pigmentosa, retinal detachment, glaucoma, Leber congenital amaurosis and hereditary optic neuropathy. In all of these diseases, XIAP gene therapy has been shown to protect cells in the retina, prevent cell death, and allow for normal cell function. XIAP gene therapy has tremendous potential to be used to treat various retinal diseases.
Dr. Tsilfidis’s team is close to conducting human clinical trials for XIAP gene therapy, and the disease they would like to target in the first human clinical trial is retinitis pigmentosa. Why? Because it has been shown that XIAP gene therapy has been effective in slowing down disease progression for many different types of RP. The path to a clinical trial has many steps: scientists start by performing experiments in a dish, and then study the toxicity of the virus they will use to deliver the gene therapy. These early discovery models help scientists figure out the dosage of the therapy and how best to deliver the virus in patients’ eyes. Dr. Tsilfidis hopes that clinical trials of XIAP gene therapy will begin sometime in the next three years.
Dr. Jean-Yves Deslandes has over twenty-five years experience in clinical development, with seven of those years in ocular gene therapy. He represents HORAMA, a small French biotechnology company that was created in 2014 by a person with vision loss who wanted to help push research forward.
HORAMA is currently developing a gene therapy called HORA-PDE6B to treat retinitis pigmentosa caused by mutations in the PDE6B gene. In order to take this therapy to the clinical trial phase, the team first had to find and enroll the right patients. This can be difficult because these early trials often have very specific inclusion criteria. They were able to enroll 7 people in a Phase I/II trial and are hoping that this study will show safety and efficacy in order to gain approval for a larger Phase III trial.
Why are there only clinical trials for certain mutations?
Patients often assume that if there is a breakthrough in gene therapy for one mutation, it will be able to treat other mutations. Dr. Stasi says that while such breakthroughs do give an advantage, they do not automatically provide a solution for multiple mutations. Ideally, researchers would like to treat all mutations, but there is a wide range of complexity in inherited retinal diseases. Researchers prefer to start with diseases and mutations that are the most straightforward and have the highest probability of success before tackling conditions that are more complex.
It is encouraging that Luxturna has been approved in the U.S. and Europe because the treatment is a “proof of concept” – it shows that gene therapies can work when all the right elements are in place. We still have a long way to go in researching and developing therapies to treat the diversity of inherited retinal diseases, which are caused by mutations in more than 250 different genes. It is also important to remember that these breakthroughs do not happen in a vacuum. For example, while Spark Therapeutics successfully developed Luxturna, three other teams working on the same gene were not successful in moving a treatment forward.
This highlights even further the importance of Dr. Tsilfidis’ work. The diseases that are currently being treated with gene therapy target a specific gene, which can be very rare. Dr. Tsilfidis’ research is a more general approach to gene therapy: XIAP gene therapy stops the death of photoreceptor cells, which occurs in a number of different retinal diseases and genetic mutations. New strategies like this, which target a common feature of a disease, have the potential to benefit a wide range of patients that may not share the same genetic mutation.
Can I participate in more than one clinical trial?
As the pace of clinical trial recruitment increases, many patients are curious about whether they can participate in more than one clinical trial. Dr. Tsilfidis explains that participation in clinical trials depends on two factors: the disease being treated and the virus that is being used to deliver the treatment. Gene therapy treatments are administered by injecting a solution directly into the eye, either into the vitreous, which is the gel-like substance filling the eye, or behind the retina. Where the virus is delivered will determine if the body will have an immune response to that virus. Once you have developed a response to a virus, you cannot be treated again with the same or similar viruses because your body will reject the treatment.
In order to qualify for any gene therapy, a person must have some photoreceptor cells left to treat. If a disease is so far advanced that all the photoreceptors have died, then the person would no longer be a good candidate for gene therapy. This is where innovative treatments like XIAP gene therapy come in. In one research model it was shown that if XIAP therapy is administered to a person early on it will increase the survival of photoreceptors, making them a good candidate for future therapies that target their specific mutation.
How are patients involved in determining if a treatment is working?
Patient involvement is a critical factor in determining the success of a potential treatment. Dr. Stasi explains that success in clinical trials used to be measured only by changes to visual acuity. This result is easy to measure in diseases that are relatively more straightforward. However, rare inherited retinal diseases are much more complicated, as they affect more parameters of vision: visual acuity, visual fields, night vision, colour vision and so on. All these factors need to be taken into consideration when assessing the effectiveness of a treatment. This means that patient reported outcomes are more valuable than ever. As a community, we need to demonstrate positive outcomes not just in terms of numbers, but by illuminating what these treatments mean to people affected by blinding eye diseases. If we cannot show value to health authorities and payers, these treatments will not reach the people that need them.
Before clinical trials can happen, researchers need to gather more information about a disease and how it affects people. Natural history studies are non-interventional studies (no treatment) that follow a group of patients over time to better understand the disease and gain insight into how it might be treated. Dr. Stasi encourages people affected by inherited retinal diseases to consider participating in one of these studies. Even if you are not receiving a gene therapy now, you will be able to contribute to the development of ideas that could lead to a treatment down the road.
Dr. Deslandes affirms that success comes from collaboration between industry, scientists, clinical teams and patients, not only to push research forward, but to demonstrate to government health authorities and payers that these treatments are valuable.
If I have a diagnosis of an inherited retinal disease what can I do?
This is the most commonly asked question from IRD patients. Even though gene therapy is not available in Canada yet, new treatments are on the horizon. There are a few things people can do now to get prepared. Firstly, Dr. Tsilfidis recommends joining the FBC Patient Registry. Not only does the Registry allow participants to be the first to hear about reputable trials for their condition, but it also allows researchers to determine how many people in Canada would be a good candidate for a particular treatment. To find out more about the FBC Patient Registry, visit this webpage: https://www.fightingblindness.ca/patient-registry/.
Dr. Green also encourages patients to get their genetic testing done. Even if you have a clinical diagnosis it is important to find out the genetic basis of your disease. For example, a clinical diagnosis of RP could be caused by a mutation in one of approximately 65 genes. In order to qualify for a clinical trial for gene therapy you must know your “genetic diagnosis” – that is, the gene mutation(s) that are causing your disease. To get genetic testing, visit your ophthalmologist. For more information about genetic testing, read our primer on Genetic Testing for Inherited Retinal Diseases. More information about how to get genetic testing in your province is coming soon, so stay tuned to our website.
Jack McCormick’s advice is to engage with the people and politicians in your community to increase awareness about the latest developments in vision research. We need to ensure that our policy makers know how close we are to having impactful treatments, and we need their support to ensure that these new treatments will be accessible to the people in Canada who need them.
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