Gene Therapy in Retinal Diseases

Several presentations that took place at AAO 2019 discussed the use of gene therapy.

On Oct. 13, researchers presented a poster, “Suprachoroidal Delivery for Ocular Gene Therapy: Nonclinical Experiments Evaluating Nonviral DNA Nanoparticles,” detailing findings regarding chorioretinal cell transfection of suprachoroidal (SC) injections of nonviral DNA nanoparticles (DNPs). Two studies were conducted: one in nonhuman primates (NHPs) and the other in rabbits (n = 4 for each). Subjects received SC 0.1 mL via injection of saline, ellipsoid-shaped DNPs, or rod-shaped DNPs. DNPs contained one copy of plasmid DNA with a polyubiquitin C/luciferase transcriptional cassette. Bioluminescence assay was used to analyze luciferase activity in ocular tissues. In both studies, the subjects with SC-injected eyes presented luciferase activity in the retina and choroid. In NHPs, luciferase activity persisted with ellipsoid-shaped DNPs at day 22. In one week, rabbits with SC-injected DNPs and subretinal rod-shaped DNPs presented similar luciferase activity.

A second poster presented Oct. 13, “The PIONEER Study: A Phase 1/2 Optogenetic Retinal Gene Therapy Clinical Trial for Nonsyndromic RP,” provided protocol and first safety data from PIONEER, an open-label, dose-escalation, phase 1/2a study of patients with end-stage nonsyndromic retinitis pigmentosa who underwent gene therapy and treatment with a medical device. According to the researchers, this study is the first of its kind. The drug product, GS030-DP, is an optogenetic gene therapy administered using a modified AAV2 vector. GS030-DP is used in conjunction with visual interface stimulating goggles (GS030-MD). No safety signals arose when the first group of three patients received GS030-MD at 5E10 vg/eye.

A paper presented on Oct. 14 shared early outcomes from a study of the effects of an AAV8 viral vector encoding retinitis pigmentosa GTPase regulator (RPGR) in the treatment of X-linked retinitis pigmentosa. Part one of the study, titled “A Dose Escalation (Phase 1), and Dose Expansion (Phase 2/3) Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using an Adeno-Associated Viral Vector (AAV8) Encoding Retinitis Pigmentosa GTPase Regulator (RPGR),” was an open-label 3+3 six-dose escalation study with 18 patients. Preliminary data indicate that all patients tolerated AAV8-RPGR. There were 65 adverse events (AEs), of which 20 were unrelated and nonocular. The majority (n = 52) were mild and most (n = 40) were resolved; 18 events may have been related to surgery and 13 to treatment. A serious AE has resolved and pertained to a moderately severe decrease in visual acuity of unknown relationship. Microperimetry improved (≥ 7 dB increase at ≥ 5 of central 16 loci) at higher doses. At one month, improvement was observed in six of 12 treated eyes compared to one of 12 untreated eyes; at three months, four of 12 treated eyes compared to and zero 12 untreated eyes; and at six months, four of 11 treated eyes versus zero of 10 untreated eyes. The authors concluded that because of the favorable safety presented in part one of the study, part two will continue as planned.