Gene therapy to treat retinal degenerations is alive and well. Dozens of centers around the world are studying subretinal and intravitreal gene delivery, and more than 1,000 patients are enrolled in trials.
When considering accomplishments recorded in the arena of gene therapy, the “firsts” are impressive.
Voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) was the first gene therapy to receive FDA approval and EU approval to treat an inherited disease-Leber’s congenital amaurosis (LCA), an autosomal recessive blindness-in the United States and Europe.
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The clinical trial of voretigene neparvovec-rzyl was the first to enroll pediatric subjects with a non-lethal disease.
The drug, according to Jean Bennett, MD, PhD, was the first to develop a path for the development of genetic treatments for blindness and provided motivation for ophthalmologists and insurers to carry out genetic testing.
Dr. Bennett is director of the Center for Advanced Retinal and Ocular Therapeutics, professor of ophthalmology and professor of Cell and Development Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
Over the previous three decades, seeval vehicles to deliver gene therapy have been tested; the one that stood out in many studies was the adeno-associated virus (AAV), a single-strand virus that is not disease-causing in animals or humans and can infect post-mitotic neurons and dividing cells, Dr. Bennett said.
When injected by subretinal injection, the AAV vector delivers the promoter and the gene under study, and this blueprint ultimately makes its way to the nucleus as a stable episome.
“There has been huge progress over the years,” she said. “There are now 271 genes identified that, upon mutation, cause retinal degeneration.”
RPE65 was identified as being mutated in 2007 in humans with early-onset retinal degeneration. Many spontaneously mutant and genetically engineered animal models are also under study.
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The clear documented improvement in vision in both the dogs and then the children with RPE65 mutations paved a clear path to FDA approval of the drug to treat LCA.
RPE65 mutations cause progressive retinal degeneration beginning with early-onset night blindness and nystagmus among other symptoms in the dogs and children with the naturally occurring disease.
The effects of the gene therapy were readily apparent in the dog model of LCA. Before injection, the dogs had no pupillary light reflex when the eye was illuminated; after treatment, there was a brisk pupillary light reflex and the dogs were able to negotiate their way around a room without bumping into objects, which was impossible previously.
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A 38-gauge cannula is used to deliver the reagent, which causes a localized retinal detachment that serves to deliver the AAV to the targeted cells.
Children who were candidates for treatment also attempted to negotiate their way around a mobility course before treatment; after treatment they moved through the course with no problem. This experiment was fine-tuned and validated in a separate study, Dr. Bennett recounted, and later used as the primary outcome in a phase III trial.
“The outcome measure showed robust statistical improvement and led to the approval of voretigene neparvovec-rzyl as a drug for LCA,” she said.
Individuals treated with voretigene neparvovec-rzyl showed marked improvements in light sensitivity, visual fields, and visual acuity. Dr. Bennett described one young man, a singer, who prior to treatment, was led onto the stage to perform and was unable to interact with and make eye contact with the audience.
Following treatment, he went on to develop a singing career, won a segment on the television talent show, “America’s Got Talent!” and is progressing further in composing and performing.
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Trends in gene therapy
Having an animal model for LCA was serendipitous. But what happens when no such model is available?
Dr. Bennett noted there is no animal model.
“We can take advantage of induced pluripotent stem cells, grow them in a dish, dedifferentiate them, and then differentiate them along a retinal-specific path, and develop a gene therapy that is tested in a dish,” she said.
If that effort is successful, the next step is safety studies in wildtype animals and a gene therapy clinical trial.
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Dr. Bennett and colleagues followed this path for choroideremia and ultimately conducted a clinical trial for the disease. Other groups are also following their lead.
What happens when a disease is not autosomal recessive or X-linked recessive?
“With diseases that are autosomal dominant, where there are gain-of-function mutations, this is a lot more challenging and may require removal of the disease-causing gene and addition of a new one or gene editing,” according to Dr. Bennett.
Another approach may be by manipulating the mutant gene sequence. Editas Medical is currently enrolling patients in a clinical trial of LCA10 using this process.
In order to start treating the numerous other retinal degenerations, Dr. Bennett pointed out the need to start targeting pathways.
“We can potentially deliver neurotrophic factors to delay apoptotic cell death,” she said. Some research groups are investigating this avenue.
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Pathways for wet age-related macular degeneration also can be targeted. RGX-314 developed by Regenxbio is a one-time subretinal anti-vascular endothelial growth factor (VEGF) gene delivery treatment that may possibly eliminate the need for frequent administration of anti-VEGF injections.
Another ambitious project involves optogenetic therapy that may possibly treat end-stage retinal diseases in patients with no viable photoreceptors.
Amid these developments, Dr. Bennett said the future of gene therapy is very bright.
“Gene therapy is alive and well. Dozens of centers around the world are studying subretinal and intravitreal gene delivery,” she said. “More than 1,000 patients are enrolled in trials to date.”
Read more by Lynda Charters
Jean Bennett, MD, PhD
Dr. Bennett is a founder of Spark Therapeutics but receives no financial compensation.