Eyeworld

I GENE THERAPY N FOCUS 30 | EYEWORLD | SEPTEMBER 2020 by Liz Hillman Editorial Co-Director What's available? Luxturna (Spark Therapeutics) became the first gene therapy approved to treat a hereditary genetic disease in the U.S. in 2017. This gene therapy delivers a functional RPE65 gene to retinal cells via an adeno-associated virus vector. Luxturna treats patients with biallelic RPE65 mutation-associated retinal dystrophy, which affects between 1,000 and 2,000 patients in the U.S. People with this autosomal recessive con- dition experience progressive vision loss from a young age that can become completely blinding. Dr. Ciulla, who was the medical strategy lead of ophthalmology for Spark Therapeu- tics, said the introduction of Luxturna brought novel paradigms to clinical ophthalmology. One was a new endpoint called multiluminance mobility testing, which he explained reflects a patient's ability to navigate in different lighting conditions. Another new paradigm was sub- retinal surgical administration; when Luxturna became available, Dr. Ciulla said ocular gene therapy treatment centers had to be established with staff who were trained to administer the therapy. A third new paradigm involved reim- bursement for potential one-time therapies. Spark Therapeutics, Dr. Ciulla said, worked to help develop different payment models for the drug, as the current healthcare system is not equipped to properly value new therapies that yield long-lasting benefits in one administration. Because most of the research toward gene therapies is for rare, inherited disorders, such as RPE65 mutation, Dr. Sohn noted that the therapy is often expensive. "The price of the medicine is a challenge for companies to continue doing research or to get approval because of the cost they have to project in terms of charging private insurance carriers and the government," said Dr. Sohn, a clinical investigator for the Phase 2/3 Luxtur- na trials. However, he went on to describe the long-term economic benefits to the individual, family, and ultimately the healthcare system when these therapies are administered. G ene therapy is the holy grail for an inherited disease, said Thomas Ciulla, MD. And the eye is a great target for gene therapies for many reasons. "The reason ophthalmology is particularly attractive is because the eye loans itself well to study," Dr. Ciulla explained. "It's an enclosed organ. It's immune privileged against a viral vector, especially in the subretinal space. There is sophisticated diag- nostic technology where we can monitor the structure and function of the retina quite well. Viral vector generally does not meaningfully travel to different areas of the body (at least not significantly), so there is limited risk of an immune reaction elsewhere." Elliott Sohn, MD, who also mentioned sev- eral of the reasons listed by Dr. Ciulla, said that one of the reasons the eye has been able to gain a foothold in gene therapy research is that it is relatively easy to access. What's more, there are many rare, blinding retinal diseases that don't have any treatment available. "The other advantages are that we can diagnose genetic disorders at a relatively high rate of accuracy. We can test some of these disorders in a dish first. We can develop treat- ments in a lab, then test them on animals, stem cell based retinal cells, as well as human explants (cadaveric retinas) and see the effects of these therapies. Because we're trying to affect one or maybe two layers of cells and these cells are laid out in a laminar pattern, we can try to address the problem directly in that cell type by bring- ing that therapy to the specific region needed. That we have a high ability to target a certain area of disease with a treatment that might last indefinitely, that they don't have to be on much immune suppression, and that we're able to demonstrate these things in the laboratory before we go to humans are some of the advan- tages of gene therapy in ophthalmology." As such, gene therapy for ocular diseases is a significant area of research. In fact, the first gene therapy to receive FDA approval for an inherited disease is for an ocular condition. Gene therapy making progress in ophthalmology At a glance • Gene therapy has the potential to be a "one-and-done" treat- ment for rare, inherited retinal disorders and potentially for disorders with a significant treatment burden, such as wet AMD. • The eye lends itself well to gene therapy treatment, in theory, for many reasons, including it being a closed system that has elements of immune privilege with a large number of identified genetic mutations that could be targeted. • Currently, there is only one FDA-approved gene therapy for an inherited retinal condi- tion (Luxturna, Spark Thera- peutics), but several others are in the pipeline. About the doctors Thomas Ciulla, MD Volunteer clinical professor of ophthalmology Indiana University School of Medicine Indianapolis, Indiana Elliott Sohn, MD Associate professor of ophthalmology and visual sciences University of Iowa Iowa City, Iowa

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