Humoral immune response to AAV5-RPGR (botaretigene sparoparvovec) gene therapy in RPGR-associated X-linked retinitis pigmentosa

Abstract

Purpose : Immunogenicity is a potential concern with vector-based gene therapies, as it may impact treatment success. Here we report baseline and treatment-emergent (TE) antibody status against the viral capsid of the adeno-associated virus vector (AAV5) and the retinitis pigmentosa GTPase regulator (RPGR) transgene following AAV5-RPGR gene therapy for RPGR-associated X-linked retinitis pigmentosa (RPGR-XLRP) in a phase 1/2 trial.

Methods : The phase 1/2 trial was an open-label, dose-escalation study assessing the safety of AAV5-RPGR gene therapy in males (aged ≥5 years) with confirmed RPGR-associated XLRP (NCT03252847). Participants (N=45) received 1 of 3 doses of AAV5-RPGR: 1.0×10¹¹ vg/mL (low, n=18), 2.0×10¹¹ vg/mL (intermediate, n=23), and 4.0×10¹¹ vg/mL (high, n=4) in volumes ranging from 0.1-0.8 mL. Humoral immunogenicity after AAV5-RPGR administration was assessed through 6 months. Serum samples were collected for the assessment of antibodies to the AAV5 capsid, neutralizing antibodies (NAbs) to the AAV5 capsid, and antibodies to RPGR at baseline and Weeks 4, 13, and 26. Immunogenicity screenings were performed on serum samples; a confirmatory test was performed on positively screened samples and, in confirmed positive samples, antibody titers were ultimately quantified. Participants positive for TE antibodies were defined as those with either treatment-induced antibodies or a 4-fold increase of titer from baseline at any time point through Week 26.

Results : Overall, 20/45 participants were positive at baseline for antibodies to the AAV5 capsid (Table), with the highest baseline titer being 1:20480. Five of 45 participants were positive at baseline for NAbs to the AAV5 capsid, with the highest baseline titer being 1:80. Through 6 months, 21/45 participants had TE antibodies to the AAV5 capsid, with the highest peak titer being 1:20480. Among these 21 participants, 9 were positive for TE NAbs to the AAV5 capsid, with the highest peak titer being 1:40. Through 6 months, 6/45 participants were positive for TE antibodies to the transgene RPGR, with the highest peak titer being 1:14.

Conclusions : No trend was identified from this study that antibody status is correlated with dose. Findings did not seem to deviate from those reported for voretigene neparvovec.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.