AAV5-RPGR (botaretigene sparoparvovec) gene therapy for X-linked retinitis pigmentosa (XLRP) demonstrates localized improvements in static perimetry

Abstract

Purpose : Subretinal injection of AAV5-RPGR gene therapy in participants (pts) with XLRP aims to target as much of the structurally intact retina as possible within the posterior pole. We assessed whether the topographically treated area of the retina (within the bleb) functionally improved over time compared to the untreated surrounding area (outside the bleb), as measured by photopic static perimetry of all tested loci.

Methods : Pts in study MGT009 (multicenter open-label Phase 1/2 trial; NCT03252847) were given 0.3-0.8 mL of AAV5-RPGR subretinally at 1 of 3 doses to the worse-seeing eye in the study dose-escalation phase; maximal coverage of structurally intact retina was achieved with >1 retinotomy, if needed. Location/extent of blebs were documented with intraoperative video. Retinal sensitivity (Octopus 900 full-field static perimetry) was compared within/outside the bleb(s) within 30-degree hill-of-vision (V30) at baseline through 12 mo for 2 intermediate dose pts. To create bleb overlay images, the hill-of-vision surface was superimposed onto the color fundus image; bleb locations were outlined by the surgeon.

Results : Pts 005 and 007 (male; 33 & 27 years of age, respectively) were analyzed. Pt 005 received therapy in a single bleb, while Pt 007 received 4 blebs to allow for maximal coverage. At 12 mo compared with baseline, V30 in total in the treated eye improved in Pt 005 (7.56 dB-sr vs 9.50 dB-sr, +25.7% improvement) and in Pt 007 (9.54 dB-sr vs 10.18 dB-sr, +6.7% improvement). Within the bleb area(s) within V30, improvements were demonstrated in both patients (Pt 005: 1.94 dB-sr vs 2.60 dB-sr, +33.8%; Pt 007: 3.85 dB-sr vs 4.06 dB-sr, +5.4%). Outside the bleb area within V30, hill-of-vision also improved in Pt 005 and Pt 007 (22.9%; +7.5%, respectively). These data are consistent with the expression of a functional RPGR protein.

Conclusions : Increases in baseline-subtracted retinal sensitivity at 12 mo (within/outside the bleb area within V30) indicate improvements in photoreceptor function suggesting local efficacy of AAV5-RPGR gene therapy. The treatment effect may extend beyond the margins of the bleb following surgery owing to subretinal extension before retinal reattachment. Further development of this therapy is warranted.

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