A Genetic Revolution for Ophthalmology

Gene therapy could lead to treatment for a number of inherited retinal diseases.

ChristineKay-sm.pngEditor’s note: Christine Kay, MD, is a vitreoretinal specialist with Vitreoretinal Associates in Gainesville, Florida. Dr. Kay reports travel reimbursement from Spark Therapeutics. Reach her at

On October 12, 2017, an FDA advisory panel voted unanimously in favor of Spark Therapeutics’ voretigene neparvovec (Luxturna) retinal gene therapy for the treatment of biallelic RPE65-mediated inherited retinal disease (IRD). The FDA will likely follow this advisory panel’s recommendation, and it will give a final response by January 2018 regarding its approval status. This will be the first retinal gene therapy to be approved by the FDA, a historic breakthrough for ophthalmology and for the visually impaired, and the first FDA-approved gene therapy for a genetic disease. In August, the FDA approved Kymriah (tisagenlecleucel), a cell-based gene therapy, for a type of acute lymphoblastic leukemia, marking the first gene therapy approval in the United States.

Physicians and Patients Speak Out

I spoke at the advisory panel’s public hearing as a physician in support of this therapy. Spark reimbursed my travel for this meeting, but otherwise I have no financial relationship with Spark. I canceled my clinic day at Vitreoretinal Associates in Gainesville, Florida, and flew to this meeting in Washington, DC, because of my belief in this product and my desire to see this therapy approved so that my patients who have this disease can be treated.

As a vitreoretinal surgeon who specializes in IRD, I follow many patients with RPE65-mediated IRD. This is a devastating disease that presents typically at birth with night blindness, decreased visual field, and decreased light sensitivity, and progresses rapidly to near-total blindness by adolescence or early adulthood. Currently there is no FDA-approved pharmaceutical treatment for this disease. The Argus II Retinal Prosthesis System (Second Sight), a retinal prosthetic device approved for patients who have already lost all vision to the point of bare light perception, is the only treatment currently available for this disease.

As I stated in my presentation during the open public hearing at the FDA advisory committee meeting, I am convinced by the phase 3 trial data that voretigene is safe and effective, and I would recommend this treatment to my patients. These patients, without treatment, will progress to blindness. The data showed significant improvement at 1 year in the outcome measures chosen to address the potential improvement in rod function that would be expected from therapy with this product, including the multi-luminance mobility test (MLMT; primary outcome measure), full-field light sensitivity test (FST), and Goldman visual fields.1 MLMT and FST have remained stable for at least 4 years, according to data presented by Spark cofounder and president Katherine High, MD, at the public FDA advisory committee hearing on October 12, 2017.    

When we look at the safety data of the phase 3 trial, there were no product-related serious adverse events and no harmful immune responses in the 31 patients treated. Ocular adverse events were mild, and expected. Four patients developed a cataract and 2 patients developed retinal tears, which were attributed to the surgery. Five patients had mild increase in intraocular pressure and only 2 patients developed ocular inflammation, which was mild. This is an excellent safety profile. As a physician counseling patients, I would feel extremely comfortable presenting this information to them and recommending this treatment.

I was particularly struck by the stories of patients who spoke at this public hearing session. These were patients who had been treated in the phase 3 trial, who one after another stood up and said that after treatment they were able to throw their white canes away, and suddenly were able to see faces and details and colors they had never seen. One young lady got onto the varsity soccer team, and another young lady stated she gained the confidence in her future to complete her master’s degree, when prior to treatment these options would likely not have existed for these patients.

All of these patients had lived their lives expecting and waiting to go blind, and now after treatment, an entirely new future was open to them, with vision not only stabilized but improved. Invariably, these stories demonstrated that this therapy had changed their lives, and allowed them to face a future not only with improved vision, but now with new independence and confidence affecting all aspects of their existence and interactions with others. Just imagine what a life change it would be to see facial expressions for the first time, and to leave the stigma of your white cane behind. Even though I’d heard enough about this therapy and was so convinced by the data that I was motivated to speak at an FDA hearing in support of it, I don’t think I fully realized the multifaceted impact it was making on the quality of life of these patients until I heard them tell their stories. 

A Convergence of Research and Opportunity

Objectively, RPE65-mediated IRD was the perfect disease, and voretigene neparvovec the perfect therapy, to make it this far toward FDA approval. RPE65-mediated IRD is a devastating disease (natural history is progression to blindness) and patients as well as physicians are desperate for a treatment. There is a decades-long history of basic science advancements in the field of gene therapy with adeno-associated viral (AAV) vector, our most well-established virus for gene delivery. The target cell in this disease (the RPE) can efficiently be transduced with AAV, and the environment for delivery (the subretinal space) is relatively immune privileged. With the luxury of excellent murine and large animal disease models, and years of preclinical supportive data depicting that these models would rescue the condition via AAV therapy, everything fit together.

However, had it not been for funded basic science research to pave the way, and a key team of energetic, motivated, tireless individuals to dedicate their careers and lives to this retinal gene therapy, none of this would have come to fruition. The team included AAV expert Jean Bennett, PhD, and Spark cofounder and president Dr. High, who was the key presenter during the October 12 FDA hearing, and who also identified Dr. Bennett’s scientific breakthrough and put into motion the steps that led to launching the human clinical trials.

Also integral to the success of this study was the clinical and surgical prowess of lead principal investigators Albert Maguire, MD and Steven Russell, MD, and the efficiency and perseverance of Spark Therapeutics, the company that has led this product into the FDA approval process. Assuredly other companies will follow Spark’s model as they continue to work toward new gene therapy products for the multitude of other IRDs that still need therapies.  

A Clear Strategy

What specifically did Spark do right? First, this company identified the key players, understood the preclinical data, and invested in the science that showed the best likelihood for success. Second, they put brilliant and efficient people in leadership positions – the most remarkable to me was Dr. High. Watching this woman lead the entire show through a grueling and intensive day of questioning at the FDA hearing was more than impressive. She knows the product and the disease, she knows the data, and she was able to deliver. Third, Spark recognized the importance of genetic testing and created an initiative called “ID your IRD” ( to provide free genetic testing to patients with certain retinal inherited diseases (this is certainly not an all-inclusive panel, but does test for most Leber congenital amaurosis genes, of course including RPE65). This was a forward-thinking way to identify RPE65-affected individuals in the United States.

Perhaps most importantly, Spark worked with the FDA to design and validate a novel “functional vision” outcome measure, necessary to evaluate visual improvement in this population of severely visually impaired patients. This was the multi-luminance mobility test, which was the primary outcome measure in the phase 3 trial. This test was designed because our most historically respected outcome measure, visual acuity, may not be as relevant to visual function, or as readily measured, in this population of patients with RPE65-mediated disease. Visual acuity is a measure of cone function, so when a therapy is designed to target RPE cells and most likely restore function to rod cells via its fundamental mechanism, visual acuity is likely NOT an ideal outcome measure. This novel outcome measure, which was received with favor by the FDA advisory panel experts on October 12, was groundbreaking from an ophthalmologic clinical trial standpoint. We have finally learned, as a field, that there may be more to “vision” than an ETDRS chart! This point alone is a game changer for all future ophthalmologic research.

Gene Therapy and the Future of Retina Practice

What do I predict will change in our field, as a result of this impending FDA approval of our first retinal gene therapy product? I think there will be a genetic revolution within the field of ophthalmology, with an explosion in the desire and need for genetic testing for IRD, and increased interest among retina specialists in IRDs (admittedly now an area with very few specialists across the country). Perhaps there will even be an increase in the number of vitreoretinal surgeons interested or involved in this field, with increasing awareness of the importance of surgical delivery in gene therapy. 

Voretigene neparvovec involves a vitrectomy with subretinal injection, as do the majority of other retinal gene therapy products currently in phase 1 or 2 trials, such as those in gene therapy trials for achromatopsia (NCT02935517, NCT02599922), Stargardt disease (NCT01367444), choroideremia,2 and Usher syndrome (NCT01505062). There are opportunities for equipment improvements, subretinal cannula improvements, and improved subretinal injection automated injection platforms. Although a subretinal injection is a procedure that any well-trained vitreoretinal surgeon should be able to perform, there are certainly details of this technique that can be optimized and standardized.

The importance of the surgical delivery – specifically creating a 300-micron subretinal bleb in the macula of a phakic, pediatric patient with a retinal degenerative disease – certainly should not be minimized as a key part of the therapy. Per the FDA hearing, Spark plans to work with the FDA to provide a training module for surgeons as this product, once approved, is commercially released. Additionally, at the hearing there was mention of first releasing the product to “centers of excellence” (these were not specifically identified by Spark) such that the surgical procedure can be optimized and standardized upon initial release of the product. I see the value in this, and if you look at Second Sight’s commercial release of the Argus II Retinal Prosthesis System, a very similar model was followed. I would also expect that as more experience is gained with this treatment after release of the product, that access to this therapy would be increased. 

It is exciting to be on the brink of seeing the first retinal gene therapy product become FDA approved. It was a monumental moment for all when the unanimous vote was passed by the advisory panel in favor of voretigene. What a breakthrough it will be if this therapy is FDA approved and we can prevent patients with RPE65-mediated IRD from going blind.

The door has opened to the field of retinal gene therapy. We are living in a new era of understanding of the genetic nature of diseases previously just given descriptive names, an era in which we no longer send our IRD patients home and tell them, “Sorry, there is nothing we can do for you.” We now have hope, not only for RPE65-mediated disease, but for so many retinal genetic diseases that will assuredly follow.


  1. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.

  2. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129-1137.