No significant visual gains seen with PDE6A gene supplementation in early-phase trial

A new clinical study¹ published in the British Journal of Ophthalmology found that a subretinal gene therapy to treat patients with PDE6A-associated retinitis pigmentosa (RP) using an adeno-associated virus (AAV) vector encoding PDE6A (AAV8.hPDE6A) did not improve visual function over 1 year and posed risks, including central retinal thinning and visual acuity decline, according to the investigators. The study was led by first author Felix F. Reichel, MD, from the University Eye Hospital and the Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.

PDE6A-associated RP, a rare form of inherited retinal disease (IRD), is characterized by nyctalopia, visual field defects, and significant loss of visual acuity (VA). The disease primarily affects the rod photoreceptors, followed by secondary loss of cones,² the investigators explained.

There currently is no treatment for this form of retinal disease, which represents about 1% of patients with recessive RP.^3-8 “However, among the investigated treatment modalities for IRDs, gene supplementation therapy shows promise. This approach has been successfully employed in RPE65-associated IRD, leading to the approval of voretigene neparvovec, an adeno-associated virus (AAV) vector-based gene therapy administered via subretinal injection,⁹ they said.

In light of the success of voretigene neparvovec, they developed and tested what they described as a comparable treatment concept for PDE6A-associated RP.

An AAV8-pseudotyped AAV2 vector was used to deliver PDE6A cDNA (complementary deoxyribonucleic acid) under the control of a human rhodopsin promoter (AAV8.hPDE6A) developed to target the rod photoreceptors with the goal of restoring their function and preventing secondary cone degeneration, the authors explained.

Reichel and colleagues pointed out that before their clinical trial, proof-of-principle studies conducted in small and large animal models showed functional rescue and morphological preservation.^10-12 In the study under discussion, they evaluated the safety and efficacy outcomes of the treatment.

Phase I/IIb clinical trial methods

Nine patients (mean age, 40.1 years) with biallelic PDE6A variants were included in an open-label, non-randomized controlled phase I/IIa trial. The patients were treated with 1 subretinal injection of AAV8.hPDE6A. Two doses of total vector genomes were tested: 1.0×10¹⁰ in 6 patients and 5.0×10¹⁰ in 3 patients. The mean baseline best-corrected VAs (BCVAs) ranged from 40 to 82 letters.

The primary study endpoint was safety, and the secondary outcomes were changes in the BCVA, contrast sensitivity, color perception, dark adaptation thresholds, visual fields, patient-reported outcomes, and chromatic pupil campimetry over 1 year.

What did the phase I/IIa study show?

The investigators reported that 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 VA loss (n=2, 1 in each dose group). The BCVA, 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 authors reported.

Reichel and colleagues reported that using the 2 doses tested, the gene therapy with AAV8.hPDE6A did not result in functional improvements.

“We did not observe preservation of cone photoreceptor function or functional rescue of rods, but in some patients, we recorded a decline in visual function and morphologic alterations of the photoreceptors that did not completely resolve over the observation period of 1 year,” they commented.

They also pointed out that because PDE6A-RP progresses very slowly and generally the decreases in the BCVA are 0.015 to 0.037 logarithm of the minimum angle of resolution annually,^2,13,14 the 12-month follow-up period may not detect slowing of the disease progression.

“It remains open whether a different dose or an optimized vector with broader transduction efficiency and/or the capability to spread laterally beyond the bleb margins, enabling subretinal treatment without foveal detachment, would lead to more positive efficacy outcomes,” Reichel and colleagues said.

They advised caution using this subretinal gene therapy for PDE6A-associated RP with detachment of the central macula and pointed out the need for further research to understand and mitigate potential adverse effects.

References

1. Reichel FF, Fischer MD, Stingl K, et al. on behalf of the RD-Cure Consortium. Safety and vision outcomes of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa: a non-randomised controlled trial. Br J Ophthalmol. 2026;110:173-9.

2. Kuehlewein L, ZoborD, Andreasson SO, et al. Clinical phenotype and course of PDE6A-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial.JAMA Ophthalmol.2020;138:1241–50. doi:10.1001/jamaophthalmol.2020.4206

3. SharonD, Ben-Yosef T, Goldenberg-Cohen N, et al. A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).Hum Mutat. 2020;41:140–9.doi:10.1002/humu.23903

4. KhatebS, Nassisi M, Bujakowska KM, et al. Longitudinal clinical follow-up and genetic spectrum of patients with rod-cone dystrophy associated with mutations in PDE6A and PDE6B. JAMAOphthalmol.2019;137:669.doi:10.1001/jamaophthalmol.2018.6367

5. WeisschuhN, ObermaierCD, Battke F, et al.Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9‐year period.Hum Mutat. 2020;41:151427.doi:10.1002/humu.24064

6. Karali M, Testa F, Di Iorio V, et al.Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.Sci Rep. 2022;12:20815. doi:10.1038/s41598-022-24636-1

7. Perea-Romero I, Gordo G, Iancu IF, et al.Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications.Sci Rep. 2021;11:1526.doi:10.1038/s41598-021-81093-y

8. Stone EM, Andorf JL, Whitmore SS, et al.Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease.Ophthalmology. 2017;124:1314–31.doi:10.1016/j.ophtha.2017.04.008

9. Russell S, Bennett J, Wellman JA, et al.Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.Lancet. 2017;390:849–60.doi:10.1016/S0140-6736(17)31868-8

10. Schön C, Sothilingam V, Mühlfriedel R, et al.Gene therapy successfully delays degeneration in a mouse model of PDE6A-linked retinitis pigmentosa (RP43).Hum Gene Ther. 2017;28:1180–8.doi:10.1089/hum.2017.156

11. Occelli LM, Schön C, Seeliger MW, et al.Gene supplementation rescues rod function and preserves photoreceptor and retinal morphology in dogs, leading the way toward treating human PDE6A-retinitis pigmentosa.Hum Gene Ther. 2017;28:1189–201.doi:10.1089/hum.2017.155

12. Mowat FM, Occelli LM, Bartoe JT, et al.Gene therapy in a large animal model of PDE6A-retinitis pigmentosa.FrontNeurosci. 2017;11:342.doi:10.3389/fnins.2017.00342

13. Kuehlewein L, Straßer T, Blumenstock G, et al. Central visual function and genotype-phenotype correlations in PDE6A-associated retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2022;63:9. doi:10.1167/iovs.63.5.9

14. Khateb S, Nassisi M, Bujakowska KM, et al. Longitudinal clinical follow-up and genetic spectrum of patients with rod-cone dystrophy associated with mutations in PDE6A and PDE6B. JAMA Ophthalmol. 2019;137:669–79.doi:10.1001/jamaophthalmol.2018.6367