Preliminary results in 18 patients undergoing retinal gene therapy for X-linked retinitis pigmentosa with codon-optimized AAV8-RPGR

Abstract

Purpose : To investigate the safety and efficacy of adeno-associated viral vector (AAV8) encoding retinitis pigmentosa GTPase regulator (RPGR) for X-linked retinitis pigmentosa (XLRP).

Methods : This study (ClinicalTrials.gov ID NCT03116113) is being conducted in 2 Parts: Part I is a Phase 1 dose-escalation study to identify the maximum tolerated dose (MTD); Part II is a Phase 2/3, assessor-masked, dose-expansion study. In Part I, subjects with genetically confirmed RPGR-associated XLRP were administered a sub-retinal dose of AAV8-RPGR. The vector used a rhodopsin kinase promoter to drive expression of a codon-optimized sequence that generated the correct full length RPGR protein. A 3+3 escalation scheme was used, with 3 subjects/dose (5×10⁹, 1×10¹⁰, 5×10¹⁰, 1×10¹¹, 2.5×10¹¹, and 5×10¹¹ gp). Part I endpoints were safety (adverse events [AEs], dose-limiting toxicities [DLTs], ophthalmic assessments, viral shedding and immunogenicity). Preliminary efficacy measures included retinal sensitivity via MAIA microperimetry.

Results : Part I enrollment has been completed and 1-month assessments are available on 18 male subjects (mean age 32.3±9.4 years). AAV8-RPGR was shown to be safe, with no occurrence of serious AEs or DLTs. In this ongoing study, 45 treatment-emergent events (TEAEs) have occurred in 15 subjects: 11 non-ocular and 34 ocular, 30 of which occurred in the study eye. No subjects have been withdrawn due to a TEAE.
Despite undergoing macular detachment, mean visual acuity recovered from 57.2±4.3 letters at baseline to 57.3±3.8 by month 1. Retinal sensitivity however improved (defined by gain of at least 7 dB in at least 5 loci) in 6 of the 18 treated eyes versus 1 untreated eye at Month 1. The largest gain was seen in a cohort 4 patient who went from 0.5 dB in his treated eye at baseline (untreated eye 0.7 dB) to 3.4 dB at month 1 (untreated eye 0.5 dB) and 6.6 dB at month 3 (untreated eye 0.5 dB). The patients with microperimetry gains also reported subjective visual field improvements in their treated eyes.

Conclusions : With a single dose of AAV8-RPGR, improvements in retinal sensitivity have been observed in XLRP patients. This unexpected finding may relate to improved cone function following successful delivery of the full length RPGR protein.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.