Double-masked, Randomized, sham-controlled, Multicenter Phase 2b study of Multi-Characteristic Opsin enabled vision restoration in patients with advanced retinitis pigmentosa: Design and Development of novel endpoints

Abstract

Purpose : In advanced retinitis pigmentosa, severe photoreceptor degeneration occurs. Optogenetics therapy offers the potential for vision restoration in these patients by photosensitizing higher order neurons. Since this approach focuses on disease phenotype versus a specific genotype deficit, it is applicable to a wide patient population. Existing optogenetic tools utilize opsins that do not generate adequate electrical current in ambient light requiring an external device for stimulation. Further, evaluation of efficacy in such low-vision patients require development of novel endpoints.

Methods : Multi-Characteristic Opsin (MCO) is an engineered opsin that is activated at ambient light levels, thereby avoiding the need for an external amplifying device and associated phototoxicity. Through the delivery of opsin encoding genes, residual retinal neurons take on the photosensitizing function of the photoreceptors. Targeting bipolar cells with MCO allows potential for greater spatial resolution. AAV2 was used to deliver MCO in advanced retinitis pigmentosa subjects. Subjects received prophylactic oral steroids prior to a single intravitreal injection of AAV2-MCO (vMCO). Safety of different intravitreal vMCO doses is evaluated using OCT, slit lamp and indirect ophthalmoscopy. Novel end points such as Y-Mobility Test (YMT) and Low-Vision Multi-Parameter Test (LVMPT) utilizing multiple luminance levels are deployed to evaluate efficacy.

Results : Approximately 50% low-vision subjects at multiple centers passed the screening criterion requiring failing of the YMT at 1 lux. The three-dimensional shape recognition by LVMPT allowed measurement of accuracy in shape recognition at different light intensities. The two different vMCO doses are well tolerated with no reported serious adverse events. Ocular adverse events include inflammation and intraocular pressure rise in few subjects, controlled via medication without requiring any surgery.

Conclusions : The vMCO doses are well tolerated with no serious adverse events. The novel endpoint measurements in low-vision subjects in a randomized and masked manner provide opportunity to evaluate the efficacy of the optogenetic vMCO monotherapy in improving functional vision in advanced RP patients.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.