Retinal gene therapy is rapidly evolving from a niche treatment for rare inherited disorders into a potentially transformative platform for common retinal diseases, according to Baruch D. Kuppermann, MD, PhD, chair of ophthalmology and visual sciences at the University of California, Irvine, during a presentation at Retina World Congress in Fort Lauderdale, Florida.
“The retina is particularly well-suited for gene therapy,” he said, pointing to the eye’s small tissue volume, relatively low dose requirements, stable nondividing cell population, and immune-privileged environment as key advantages for long-term gene expression (Figure 1).
Figure 1. There are many reasons that the retina is considered an ideal target for gene therapy, noted Baruch D. Kuppermann, MD, PhD.
Dr. Kuppermann distinguished current retinal gene therapy approaches from true gene editing, describing many retinal strategies instead as “gene programming” or “gene augmentation,” in which retinal cells are transduced to produce either missing proteins (gene augmentation) or therapeutic proteins (gene programming).
The only FDA-approved retinal gene therapy is voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics), which was approved in 2017 for inherited retinal dystrophy associated with RPE65 mutations. The therapy is delivered subretinally and introduces a functional copy of the defective gene to produce the missing protein.
Dr. Kuppermann explained that gene therapy strategies are evolving to address common retinal disorders, such as neovascular age-related macular degeneration (nAMD). Investigators are focused on what he described as a “biofactory approach,” in which retinal cells are genetically engineered to continuously manufacture anti-VEGF proteins after a single treatment (Figure 2).
Figure 2. By delivering genetic instructions to retinal cells, gene therapy may enable sustained production of therapeutic agents directly within the eye.
Current anti-VEGF therapy requires frequent injections that often lead to undertreatment and variable drug levels. In turn, gene therapy platforms seek to create sustained intraocular production of anti-VEGF agents after a single administration. Dr. Kuppermann explained how viral vector transduction may preserve steady therapeutic concentrations and reduce the “peaks and troughs” associated with repeated intravitreal injections.
He also highlighted adeno-associated virus (AAV), currently the leading platform for in vivo retinal gene delivery. AAV vectors are nonpathogenic, relatively low in immunogenicity, and capable of long-term gene expression. However, they also face important limitations, including restricted payload capacity and difficulty penetrating vitreoretinal barriers after intravitreal injection. To address these challenges, researchers are engineering next-generation AAV capsids using “directed evolution,” a bioengineering technique that simulates natural selection to identify viral variants with enhanced retinal penetration and transduction efficiency.
Figure 3. Three gene therapies for neovascular age-related macular degeneration are currently in phase 3 clinical trials.
Several investigational therapies for nAMD are already in clinical trials, including Ixo-vec (Adverum), 4D-150 (4D Molecular Therapies), and Sura-vec (Regenxbio/AbbVie), which use AAV vectors to deliver anti-VEGF transgenes (Figure 3). Dr. Kuppermann noted that engineered capsids (Ixo-vec and 4D-150) may allow intravitreal administration at lower doses, whereas wild-type vectors (Sura-vec) often require subretinal or suprachoroidal delivery.
One of the more notable findings from Dr. Kuppermann was the possible long-term durability of gene therapy. He shared a case in which ex vivo donor eye tissue from an 84-year-old patient with bilateral nAMD was treated with Ixo-vec. Investigators detected aflibercept messenger RNA expression in the macula and peripheral retina 3.5 years after a single intravitreal injection, suggesting that sustained therapeutic activity may persist for years after treatment.
Dr. Kuppermann also discussed optogenetics, an emerging strategy for advanced retinal degeneration in which AAV-delivered engineered opsins modify surviving bipolar or retinal ganglion cells (depending on the AAV vector and technology) to sense light, with the goal of improving visual function after photoreceptor loss (Figure 4).
Dr. Kuppermann cautioned that retinal gene therapy still faces important hurdles. Risks include inflammation following intravitreal administration, immunogenicity related to retinal cell transduction, and the inability to “turn off” therapy once cells are transduced. Surgical approaches such as subretinal delivery also carry procedural risks, including retinal detachment and hemorrhage. Still, the field is advancing rapidly. “We hope to see the success of gene therapy in the not-so-distant future,” said Dr. Kuppermann. RP
