Gene Therapy’s Potential for a Single Lasting Treatment of Retinal Disease

Robert E. McLaren, MBChB, discussed the promise that adeno-associated viral (AAV) vectors have shown in the treatment of inherited retinal diseases. In his ongoing research on gene therapy for choroideremia, he is following 6 patients who received a unilateral subfoveal injection of recombinant REP1 gene in an AAV2 vector.

“After administration into the subretinal space, the viral vector is expressed in the retinal pigment epithelium [RPE]—and messenger RNA, including the choroideremia gene, will be expressed in the RPE cells indefinitely,” said Dr. MacLaren, speaking at Friday’s Retina Subspecialty Day. “As far as we know, assuming the cells are dividing, [the gene expression will be maintained] for the lifetime of the individual. And that’s what’s really so exciting about gene therapy: We are potentially creating a single lasting treatment.”

Earlier this year, Dr. McLaren and colleagues presented the long-term visual acuity (VA) results of their cohort. The significant gains that they observed in 2 of their 6 subjects were maintained for at least 3-1/2 years—a testament to the durability of the treatment. “Subsequently, during this time, the fellow, untreated eye began to decline, so that, effectively, these patients have begun to swap over; and in some cases, the treated eye is becoming better than the untreated eye,” he said. (At baseline, the control eyes had better VA than the treated eyes.)

Next steps. Now that the tolerability and potential efficacy have been established, the crucial next phase is determining the best surgical technique for delivering the vector to the affected cells in the retina. There is current debate on whether to administer it as an intravitreal or subretinal injection. Although intravitreal delivery is a technically easy procedure, it appears to predispose the patient to an inflammatory immune response to the viral particles—one of the main safety concerns of AAV treatment. Subretinal injection allows for better pharmacokinetic transduction to the RPE and photoreceptors, but it is a more challenging procedure, particularly in patients with end-stage disease and, therefore, thinner retinas.

Dr. MacLaren’s team is currently developing a robotic approach that may provide the needed reliable precision for successful subretinal delivery. After a surgery has been validated, researchers will be able to establish the dosage required to see a treatment effect. With both of these goals close at hand, Dr. MacLaren believes that a new era of gene therapy is upon us.—Aliyah Kovner 

Financial disclosures. Dr. MacLaren: NightstarX LTD: C, E, O, P; University of Oxford: E, P.

Disclosure key. C = Consultant/Advisor; E = Employee; L = Speakers bureau; O = Equity owner; P = Patents/Royalty; S = Grant support.