December 06, 2017
12 min read

Outlook optimistic for uncommon inherited retinal dystrophies

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Inherited retinal dystrophies affect far fewer individuals in the Western world, in contrast to other more common and widespread retinal disorders, but the interest in therapies and treatments of inherited dystrophies is growing.

The most prevalent inherited retinal dystrophies are retinitis pigmentosa, Leber congenital amaurosis (LCA) and Stargardt disease, according to a 2012 study published in Current Genomics. Retinitis pigmentosa (RP) affects one in 3,500 to one in 4,000 people in the United States and Europe. In China, RP affects an estimated one in 1,000 people, and in India, one in 930 people. RP is usually the result of mutations in any of more than 100 genes, with the rhodopsin (RHO) gene accounting for approximately 25% of patients with autosomal dominant retinitis pigmentosa, according to the study.

Uncommon retinal diseases

Stargardt disease mostly affects children between the ages of 6 and 16 years, manifesting in about one in 8,000 to one in 10,000 individuals. Acute loss of visual clarity followed by gradual loss of central vision are the first signs of the dystrophy. The disease is caused by biallelic mutations in the ABCA4 gene, which results in the absence or insufficiency of ABCA4 protein and the accumulation of all-trans-retinal, which reacts with ethanolamine to form the fluorophore A2E, according to the study.

For Alex V. Levin, MD, MHSc, FRCSC, this is an exciting time for ocular geneticists and ophthalmologists treating rare dystrophies.

Source: Roger Barone/Wills Eye Hospital

One of the more severe inherited retinal dystrophies, LCA, is a congenital form of retinal dystrophy, affecting only two to three cases per 100,000 births but is the leading cause of inherited blindness in children, according to the American Association for Pediatric Ophthalmology and Strabismus.

The condition is most commonly inherited as autosomal recessive and can be caused by a mutation in more than 14 different genes. Rare forms of LCA, autosomal dominant forms, are caused by a mutation in the CRX, IMPDH1 or OTX2 gene, according to the Current Genomics study.

Patients with LCA commonly have severely impaired visual acuity at birth or during the first 6 months of their life.

Growing treatment market

The interest in treatments and therapies for these dystrophies has greatly expanded in the past decade, despite the limited number of individuals affected. Next-generation genetic sequencing and retinal gene therapy clinical trials may be beneficial for patients as they are developed and approved for commercial use, Hafler wrote in a 2017 study in Retina.


Many clinical trials are currently being enrolled, tested and completed for potential treatments and therapies for these dystrophies. A phase 3 clinical trial of subretinally delivered AAV vector encoding 65 kDa retinal pigment epithelium (RPE)-specific protein in patients with RPE65-associated LCA was recently completed and has shown success in improving sensitivity to light and functional vision, Hafler said in the study.

This specific gene therapy was developed by Spark Therapeutics. In October, 16 members of the Cellular, Tissue, and Gene Therapies Advisory Committee of the FDA unanimously voted that the therapy, voretigene neparvovec, showed an overall favorable benefit-risk profile for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal dystrophy.

In the clinical trial, 20 intervention patients underwent the therapy and showed functional improvement in vision with a 1.9 specified lux level improvement in bilateral mobility testing at 1 year. Additionally, seven of the 20 patients experienced a 15-letter improvement in the first eye treated at 1-year follow-up compared with none in the control group, Hafler wrote.

Potential for gene therapy

Luxturna, the proposed trade name for voretigene neparvovec, is a gene therapy vector designed to supply a normal copy of the gene encoding RPE 65-kDa protein, or RPE65, Katherine A. High, MD, president and head of research and development for Spark Therapeutics, said.

The absence of the enzyme disrupts the visual cycle and causes vision loss. Early findings include nyctalopia and loss of visual fields. Visual acuity also worsens over time, and most patients eventually progress to complete blindness, she said.

Katherine A. High

“The phase 3 study, published in The Lancet, demonstrated that subretinal injection of voretigene led to improved ability to navigate, particularly in dim lighting conditions, a gain in full-field light sensitivity, and an improvement in visual fields. Visual acuity also improved by 0.3 logMAR (three lines) in 55% of first eyes injected and 20% of second injected eyes. These improvements have persisted for up to 4 years, with observation ongoing. Currently there is no pharmacological treatment for individuals born with this rare form of inherited blindness,” High said.

The price of the therapy has yet to be determined, but High said Spark will ensure patients and their families have access to the therapy if it is approved, and the company is looking at programs to help offset the out-of-pocket costs and travel expenses to treatment centers.

According to an article published on in October, some analysts have estimated the therapy could cost around $1 million.


Exciting time for advancement

With the potential approval of voretigene neparvovec, it is an exciting time for ocular geneticists and ophthalmologists treating these rare dystrophies, Alex V. Levin, MD, MHSc, FRCSC, of Wills Eye Hospital, said.

Twenty years ago, ophthalmologists were telling patients that there was little they could do to treat their disease and that they would most likely go blind if they were diagnosed with one of the inherited retinal dystrophies. Even worse, Levin said, was when a diagnosis was not available for patients and they were left with unknown fears for the rest of their lives.

“Now, we live in a completely different world. Our diagnostic abilities are vastly, hugely improved. The ability to get someone a diagnosis through the field of ocular genetics, which is a rare field in ophthalmology — there are only 70 to 80 of us worldwide — using DNA and other forms of molecular technology to diagnose patients has greatly advanced. Our rate of being able to get a diagnosis, a DNA diagnosis, is 70% to 80%. When you consider that 30% of patients who come to see me come with a wrong diagnosis or no diagnosis, we can now turn that into, ‘This is exactly what you have, this is why it’s happened, this is what the risk is to your family members, to you, and this is what’s in your future.’ I think it’s fair to say that every patient would rather have a bad diagnosis than uncertainty,” Levin said.

A growing armamentarium

Gene therapy, retinal chip implant devices and cell therapy all offer exciting advancements for the treatment of these previously untreatable dystrophies. Especially for younger patients, there is no longer doubt whether there will be a cure, according to Levin: “It’s not if, but now a question of when.”

Levin said Spark’s RPE65 mutation gene therapy treatment, with its potential to be approved by the FDA, is a huge step for gene therapy and another important weapon in an ophthalmologist’s armamentarium.

“Over the next 5 years, the rapid advances of diagnoses will put people into categories to allow them to receive the appropriate treatment,” Levin said. “Stem cell [therapy] is already being used, and I think we’ll see advances in stem cells in the next 5 years. Other gene therapy trials will be approved, and then low vision technology is certainly advancing as well.”

Indeed, the research currently being undertaken in the fields of gene and stem cell therapy offers exciting new possibilities for treatments, High said.


“I am a hematologist, not an ophthalmologist, but I have worked for many years on gene therapy for genetic disease. I am genuinely heartened by the level of activity in this space right now. Here at Spark, and at another company, Nightstar, there are ongoing clinical programs for choroideremia. There are also ongoing clinical trials for Leber hereditary optic neuropathy, achromatopsia, X-linked retinoschisis and other diseases. So, I think we have entered an exciting time for a group of diseases that has previously been considered untreatable,” she said.

Stem cell and gene therapies

Nightstar Therapeutics is developing NSR-REP1, a gene therapy for choroideremia (CHM). According to the company, the therapy is comprised of an AAV2 vector containing recombinant human complementary DNA, which is designed to produce REP1 inside the eye.

The therapy is injected into the subretinal space of a patient with CHM and is designed to enhance expression of the REP1 protein. The company is recruiting participants for a STAR phase 3 registration trial primarily from the NIGHT study.

The New England Journal of Medicine published a study in 2016 on NSR-REP1 and noted positive results from an early phase 1/2 trial. The results showed two of six patients with CHM who received the therapy experienced improved visual acuity gains at 3.5 years after treatment. Visual acuity degenerated in each of the control eyes at 3.5 years’ follow-up.

Potential oral therapies, such as valproic acid or ALK-001, are “certainly attractive for some inherited retinal disorders,” but their use will depend on the mechanism of the genetic mutation in the patient and the causes of their disease, its stage and the bioavailability of medicine, Elliott H. Sohn, MD, of the Stephen A. Wynn Institute for Vision Research (WIVR), said.

Gene and stem cell therapies will likely have the most impact moving forward, Sohn said.

Elliott H. Sohn

“When you use biological-based agents such as gene and stem cell treatments, you can harness the power of multiple layers of retinal cells to better modulate signals that would in theory allow the highest level of visual detail possible. It will be interesting to see how broader-based treatments such as optogenetics can impact visual function, but I believe that providing gene correction for the specific mutation causing most disorders, such as RPE65-associated LCA, will have a good chance of preventing vision loss,” Sohn said.

Diagnosis is key

Having the correct genetic mutation identified and diagnosed is crucial to treatment. Gene therapy trials will continue, but most of these will not be able to help patients with extensive photoreceptor and/or RPE loss, Sohn said.


“This is where stem cell treatments could benefit patients the most. In particular, if you can use autologous retinal cells (ie, made from the person for whom they are intended) that have the genetic mutation corrected, you should have the lowest possible immune response than if [treatment] were derived from another person,” Sohn said.

Sohn and colleagues at his institute are recruiting for a treatment trial for patients with CEP290-associated LCA and will begin to enroll patients with ABCA4-associated Stargardt disease with gene replacement.

Additionally, Sohn said he is excited to continue work with his colleagues at the WIVR to develop autologous-induced pluripotent stem cell-based CRISPR gene-corrected photoreceptor cells to replace those that result in blindness from an inherited retinal disorders.

“As treatments for inherited retinal diseases are based on the genetic mutation, it is crucial that patients have high-quality genotyping done by experienced people. Ideally, it is easiest to send patients with inherited retinal disorders to someone who has expertise, but of course it can be difficult for some patients to travel great distances. The Carver Nonprofit Genetic Testing Laboratory is one place where families can even send their blood in remotely to get low-cost diagnostic testing in a very well-thought-out fashion, but it depends on the physician knowing what to order. Using this approach, we can determine the causative mutation in 76% of patients with inherited retinal diseases at an average cost of $1,200 per family,” Sohn said.

The time of physicians telling patients with RP that “there’s nothing we can do for you, you’re going to go blind” is at an end, according to Sohn, and getting patients to the right physician for evaluation and genotyping is more important now than ever.

Ophthalmology has “great innovators in retina” who have brought retinal implants to the market to treat these dystrophies, but the more the existing retinal circuitry is utilized, the better, Sohn said.

Device field also growing

Presently, the device arena will likely have the most impact on patients, Mark S. Humayun, MD, PhD, president of the American Society of Retina Specialists, director of USC Institute for Biomedical Therapeutics and co-director of USC Roski Eye Institute, said.

Retinal implant devices such as the Argus II retinal prosthesis system (Second Sight Medical Products) and the IRIS bionic vision restoration system (Pixium Vision) are basically “agnostic” and not dependent on a specifically mutated gene to provide patients with improved vision, Humayun said.

“In the next few years, I’d say 2 to 3 years, I think the sheer number of people who will be helped will be greatest in the device category. It’s not restricted to particular gene correction,” he said.

Mark S. Humayun

The Argus II, according to an FDA humanitarian device exemption, is indicated for use in patients with “severe to profound retinitis pigmentosa” who are 25 years or older, have bare or no light perception in both eyes, have a history of useful form vision, and are aphakic or pseudophakic.

The device provides electric stimulation to the retina to induce visual perception in blind subjects. The system has a miniature video camera built into a patient’s glasses to capture a scene, according to the Second Sight website.

The IRIS system, which gained CE mark in July 2016, is an epiretinal implant with 150 electrodes, powered by induction, and is compatible with next-generation visual interface and advanced signal-processing algorithms, according to the Pixium website.

“The devices will be used more because they can be used in more patients,” Humayun said. “The devices can only be implanted in patients who have very little vision left: light perception or worse in the United States, and hand motions or worse outside of the United States. Because of those types of visual acuity entry criteria, the number will still be small, but it will be bigger than the RPE65 target population. If you were to look into the next 2 or 3 years, the devices will end up being implanted in more patients than the Spark Therapeutic gene therapy approach,” Humayun said.

Humayun said the gene and stem cell therapy divisions will likely have a greater impact in patients with inherited retinal dystrophies overall, but will do so in perhaps 5 years in the future.

In a November press release, Second Sight announced the final Medicare hospital outpatient payment rate for the Argus II procedure, including the cost of the device, will be $122,500 for the calendar year 2018.

Rapidly advancing industry

The industry overall, however, is moving at an incredible rate, and the number of existing therapies for inherited retinal dystrophies provides more hope for patients now than for patients in the past, Humayun said.

“Today we have a lot more existing and future therapies for RP, which in the past, for many decades, you couldn’t do anything about. It was incurable. It’s a devastating condition because you know you’re going to lose your vision and every year you’re losing more of it, but there’s nothing that can be done. It’s really good from a patient perspective, but also from a treating physician perspective, to be in a place that you can offer therapy that didn’t exist,” he said.


Stressing to patients that these are no longer untreatable diseases is extremely important, Levin said.

Patients must realize that a diagnosis is not a time to sit back and do nothing, but a time for action and to move on a potential therapy or device to allow them to better live their lives, he said.

“We need to stress the importance of ocular genetics as a growing field in ophthalmology. There are very few fellowships in the world. We have one at Wills, but training more ocular geneticists is key. The development of the specialty is revolutionary. We want ophthalmologist to know that this specialty is there. Our hope is that we can use this resource for patients who hear from their ophthalmologists, ‘Well, you’re going to go blind’ or ‘I don’t know what you have, sorry.’ They may not even realize this resource is available for them so we want to get past there,” Levin said. – by Robert Linnehan

Disclosures: High reports she is the president and head of research and development at Spark Therapeutics and holds equity in the company. Humayun reports he is the co-inventor of the Argus II retinal prosthesis system and is involved in a stem-cell based study for macular degeneration. Levin reports he is a consultant for Spark Therapeutics. Sohn reports he receives grant support from Sanofi and Oxford BioMedica and is a clinical trials investigator for ProQR and Spark Therapeutics.

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