Optogenetics in the Clinic: PIONEER, a Phase 1/2a Gene Therapy Program for Non-Syndromic Retinitis Pigmentosa

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Martel J, Esposti SD, Boulanger-Scemama E, Galluppi F, Vernadal E, Gray D, Taiel M, Blouin L, Sahel JA

Optogenetics in the Clinic: PIONEER, a Phase 1/2a Gene Therapy Program for Non-Syndromic Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science. 2020 June 1;61(7):4491.

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Abstract

Purpose : Retinitis pigmentosa (RP) is an inherited retinal disease with >100 known mutations. In late-stage RP, cone photoreceptors degenerate, causing loss of central visual acuity and eventually blindness. GS030 is an optogenetic treatment using a drug product (GS030-DP) with a medical device (GS030-MD) in clinical development to potentially restore vision function in RP patients independent of their underlying mutation. The PIONEER study aims to evaluate the safety and tolerability of optogenetic gene therapy and a light stimulation medical device in subjects with non-syndromic RP. Methods : GS030-DP is an optogenetic gene therapy targeting retinal ganglion cells that encodes a light sensitive channelrhodopsin, ChrimsonR-tdTomato (ChR-tdT), delivered by an AAV2.7m8 vector and administered via intravitreal injection (IVT). Visual interface stimulating goggles encode images of the visual world and modulate an amplifying light source projected onto the genetically engineered retina. PIONEER is a Phase 1/2a open-label study to evaluate the safety and tolerability of GS030 in subjects with end-stage non-syndromic RP. Three dose-escalation cohorts (5E10, 1.5E11, 5E11 vg/eye) will include 3 subjects each, and an extension cohort will be treated at the highest tolerated dose. Results : Inclusion in the first cohort started in Q4 2018. Up to 1 year after treatment administration, there were no serious adverse events (SAEs) nor study discontinuations. The most common adverse events (AEs) were mild anterior chamber inflammation responsive to corticosteroid treatment, and mild sensitivity to light starting after drug product administration but before light stimulation by the goggles. The use of GS030-MD to stimulate ChR-tdT was initiated two months after administration of gene therapy and showed no safety concerns, before or after IVT with GS030-DP. Two subjects of the second cohort were injected with 1.5E11 vg/eye in Q3 2019. No serious AEs have and no unexpected AEs have been reported. Conclusions : PIONEER is the first clinical trial for RP combining the simultaneous action of a gene therapy and a medical device, a therapeutic approach independent of underlying genetic defects. Treatment was well tolerated in the first cohort, and completion of the second cohort with an intermediate dose is currently ongoing. Treatment of the third cohort at the highest dose is planned in Q1 2020.

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