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Bringing Optogenetics to the Clinic: THE PIONEER STUDY: a Phase 1/2 Gene Therapy Program for Non-Syndromic Retinitis Pigmentosa

Barrett Katz, SD


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



  1. Albert Einstein College of Medicine, NY

Introduction: Retinitis pigmentosa (RP) is a family of inherited retinal diseases involving progressive degeneration of rod and cone photoreceptors. A sustained inflammatory reaction may contribute to the underling pathogenesis of RP and further add to degradation of photoreceptors. Progressive vision loss culminates into blindness.

There are over 100 genetic mutations associated with the RP phenotype, with inheritance patterns that include autosomal dominant, autosomal recessive, X-linked, and maternally (via mitochondrial DNA) transmitted variants. There are currently no approved therapies for RP disease progression. GS030 is an investigational treatment combining both a novel gene therapy and a medical device currently in active clinical development to address this unmet medical need. The drug product of GS030 is an optogenetic gene therapy targeting retinal ganglion cells (RGCs) and encoding an optimized form of channel rhodopsin ChrimsonR, ChrimsonR‑tdTomato (ChR-tdT). Visual interface stimulating goggles, the medical device of GS030, process special “event” images of the visual world which modulate a powerful light source projected onto the genetically re-engineered retina.


Methodology: ChR-tdT is delivered by a modified AAV2 vector administered via a single intravitreal injection (IVT). The enhancing goggles are a non-invasive optoelectronic medical device which serves to provide light stimulation specifically tailored to the optogenetic protein ChR-tdT and to the RGCs; since under usual ambient lighting conditions, little or no photoactivation of ChR-tdT is expected. The function of the GS030 medical device is to process incoming visual stimuli in real-time and project them as 2-D images onto the retina.

PIONEER is a Phase 1/2a, open-label, non-randomized, dose-escalation study to evaluate the safety and tolerability of GS030 in subjects with end-stage non-syndromic RP and vision of light perception or no light perception. The worst‑seeing eye of a subject is treated with GS030. Three dose-escalation cohorts (5E10, 1.5E11, 5E11 vg/eye) include 3 subjects each, and an extension cohort with up to 9 subjects at the highest tolerated dose. Prior to injection with ChR‑tdT, a three-visit inclusion stage allows for baseline measurements, photophobia assessment, setting of pre-defined stimulation parameters of the googles, and mobility testing. The therapeutic use of the stimulating goggles starts 8 weeks after injection.

Results: The first human subject was injected with 5E10 vg/eye of ChR‑tdT in the fall of 2018. The subject reported mild light sensitivity following injection. As expected, the IVT resulted in mild anterior chamber inflammation responsive to corticosteroids and resolved by 4 weeks post injection. First use of the medical device post gene therapy was initiated two months following IVT without untoward effects or safety signals.


Conclusions: PIONEER is the first clinical trial combining the simultaneous action of a gene therapy and a medical device. As the RGCs are close to the vitreo-retinal surface, they are amenable to AAV infection following IVT, a major advantage compared to sub-retinal administration. AAV2 and AAV2.7m8 transduce a ring of perifoveal RGCs in non-human primates. A retinal optogenetic therapeutic approach independent of underlying genetic defects is of major importance in RP, given the association with a wide array of gene mutations. As RP advances, both rod and cone photoreceptors are lost, though RGCs are preserved. Under such conditions, a therapeutic intervention that converts RGCs into photo-responsive cells via an optogenetic protein offers great promise for this family of disease.


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