Gene and optogenetic therapies in retinitis pigmentosa show mixed early and long-term results

Gene and optogenetic therapies for retinitis pigmentosa reported mixed results across recent clinical studies, with UGX-201 and MCO-010 showing visual acuity improvements and AAV8.hPDE6A showing no significant visual gains at 1 year. In advanced nonsyndromic retinitis pigmentosa, a single intravitreal injection of UGX-201 was generally safe and well-tolerated and demonstrated sustained improvements in visual function within one year after administration, while 3-year follow-up from the RESTORE/REMAIN program showed MCO-010 maintained approximately 3 ETDRS lines of vision gain.

In an open-label, nonrandomized trial (ChiCTR2200062174), 9 patients with advanced nonsyndromic retinitis pigmentosa received a single 1.5×10¹¹ vg UGX-201 intravitreal injection in the eye with worse visual acuity, and the primary outcome was safety through 52 weeks. The study population comprised 5 women and 4 men, 6 patients had light perception and 3 had no light perception, and collectively they had each had a mutation in a unique gene. No serious adverse events were observed in this study. A total of 25 adverse events occurred among 6 patients, in which 24 of the events were of grade 1 severity and 1 adverse event was of grade 2 severity.

Two patients reported ocular pain and transient visual loss immediately after injection. Both patients received anterior chamber paracentesis which alleviated acute intraocular pressure elevation and restored light perception, and both cases resolved within 30 minutes. At baseline, all patients had a negative humoral response to the UGX-201 vector, but by week 52, 5 patients had developed a positive immune response. No quantifiable UGX-201 vector DNA was detected in serum samples at 52 weeks. Fundus imaging and optical coherence tomography indicated sustained structural stability without deviations from what is expected in advanced retinitis pigmentosa.

Among patients with light perception, best-corrected visual acuity decreased by 0.34 (95% CI, -1.05 to 0.37 logMAR; P = .27) from baseline to week 8, the change was maintained through week 12 at -0.35 (95% CI, -1.11 to 0.41 logMAR; P = .29), and was slightly attenuated by week 52 at -0.30 (95% CI, -1.00 to 0.41 logMAR; P = .33). A total of 2 eyes (33.3%) had a best-corrected visual acuity improvement of more than 0.3 logMAR from baseline to week 52. All patients with no light perception at baseline developed light perception between weeks 2 and 24. The study, published in the American Journal of Ophthalmology, said this was the first clinical exploration of introducing recombinant opsin into retinal ganglion cells through optogenetic therapy among patients with advanced non-syndromic retinitis pigmentosa in China.

In the randomized, controlled phase 2b/3 RESTORE trial, patients with advanced retinitis pigmentosa received a single intravitreal administration of MCO-010 at high dose (1.2 × 10¹¹ gc/eye; n = 9), low dose (0.9 × 10¹¹ gc/eye; n = 9) or sham control (n = 9), and patients who completed RESTORE were eligible to continue into the REMAIN long-term follow-up study at week 100. The primary endpoint of RESTORE was best-corrected visual acuity change from baseline at week 52. At week 52, mean best-corrected visual acuity change from baseline was 0.337 ± 0.083 LogMAR in the high-dose group (vs sham, P = .021) and 0.382 ± 0.124 LogMAR in the low-dose group (vs sham, P = .029). At week 152 of REMAIN, mean best-corrected visual acuity improvements from baseline were 0.264 ± 0.112 LogMAR in the high-dose group and 0.453 ± 0.140 LogMAR in the low-dose group. These improvements correspond to approximately 3 ETDRS lines of vision gain. No treatment-related serious adverse events were reported.

Post hoc multivariate analyses identified several baseline factors associated with greater treatment response at week 52: MCO-010 expression as measured by fundus autofluorescence imaging, baseline central subfield thickness greater than 100 μm, and disease duration of less than 30 years. Best-corrected visual acuity gains correlated with retinal transduction and MCO protein expression on fundus autofluorescence imaging, less retinal thinning on optical coherence tomography and shorter duration of disease. DVC1-0401, a third-generation, non-replicating lentiviral vector encoding pigment epithelium-derived factor, was also reported in a phase 1/2a dose-escalation trial in 12 patients with typical retinitis pigmentosa. No serious adverse events related to DVC1-0401 were identified across all 12 participants, and treated eyes showed a significantly slower rate of decline in both best-corrected visual acuity and Humphrey 10-2 foveal retinal sensitivity compared with fellow eyes (P < .05).

A separate phase I/IIa trial of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa included 9 patients with biallelic PDE6A variants who were treated with 1 subretinal injection of AAV8.hPDE6A at doses of 1.0×10¹⁰ in 6 patients and 5.0×10¹⁰ in 3 patients. The primary study endpoint was safety, and the secondary outcomes were changes in best-corrected visual acuity, contrast sensitivity, color perception, dark adaptation thresholds, visual fields, patient-reported outcomes, and chromatic pupil campimetry over 1 year. No systemic adverse events developed, and most ocular events resolved without treatment.

The persistent adverse events included small peripheral atrophic areas (n=2), disturbed color discrimination (n=3), cataract (n=1), slight central retinal thinning (n=5), and moderate visual acuity loss (n=2, 1 in each dose group). Best-corrected visual acuity, full-field stimulus thresholds, and other visual function measures showed statistically non-significant changes, with a trend toward worsening of retinal sensitivity in the treated eyes. The study published in the British Journal of Ophthalmology reported that, using the 2 doses tested, the gene therapy with AAV8.hPDE6A did not result in functional improvements and did not observe preservation of cone photoreceptor function or functional rescue of rods. Investigators advised caution using this subretinal gene therapy for PDE6A-associated retinitis pigmentosa with detachment of the central macula and pointed out the need for further research to understand and mitigate potential adverse effects.