Adeno associated virus serotype rh74 (AAVrh74) is considered a leading vector to deliver therapeutic cargo in neuromuscular diseases (NMD). Humoral pre-existing immunity (PEI) to AAVs is a key consideration for in vivo AAV gene delivery, as it may diminish the potential benefit-to-risk profile. The AAVrh74 PEI prevalence has been published in Duchenne muscular dystrophy (DMD) patients. However, the DMD population’s young age and chronic glucocorticoid steroid exposure hinder extrapolating the findings to an adult population with competent immunity, such as most patients with symptomatic Facioscapulohumeral muscular dystrophy (FSHD).
To address this knowledge gap, a cross-sectional observational study was conducted with the primary objective to better understand the seroprevalence for AAVrh74 in adults with symptomatic FSHD. The data gathered from this study are expected to aid in the clinical development of EPI-321, a single AAVrh74 vector encoding an ultracompact, catalytically inactive Cas protein fused to gene-suppressing modulators, and a guide RNA targeting the D4Z4 locus, as a potential one-time therapy for FSHD.
The total anti-AAVrh74 antibody titer was evaluated using a validated bridging immunogenicity assay, and seropositivity was defined as a titer ≥1:400. Fifty-eight adult participants with symptomatic FSHD were enrolled across the United States (4 study sites; n=48 participants) and New Zealand (1 study site; n=10 participants). Thirty-three participants (56.9%) were female. The average participant age was 46 years (range, 18.6 to 76.4 years). Ten out of 58 participants (17.2%) were seropositive for AAVrh74 per the study criterion.
The observed low PEI among adults in this study highlights the potential of AAVrh74 as an appropriate gene delivery vector for FSHD. The first-in-human study of EPI-321 for FSHD is ongoing, and clinical data are expected in 2026.