P56 Preliminary study of anti-AAVrh74 seroprevalence following gene transfer

• Published in: Neuromuscular disorders : NMD 2023-10, Vol.33, p.S72-S73
• Main Authors: D'Ambrosio, E., Tong, L., Ozes Ak, B., Lehman, K., Sahenk, Z., Mendell, J.
• Format: Article
• Language: English
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2023.07.037

The increasing number of gene therapy studies and exclusion of candidates from clinical trials highlights the potential importance of pre-existing antibodies targeting viral capsid. Viral antibodies block transduction and preclude expression of the transferred gene. Provoked immune response could also be a threat to safety. Testing patients for pre-existing antibodies, either neutralizing (Nabs) or total/binding (TAbs/BAbs), prior to gene transfer is a critical step in the initiation of a clinical trial. Previous studies assessed the seroprevalence of antibodies against different AAV subtypes in the general population and in patients receiving gene transfer. Our gene therapy studies for muscular dystrophy (DMD, LGMD) have currently shown promise for efficacy and safety, but we don't know if vector shedding post gene delivery affects the antibodies titer in family members of trial participants. This is particularly relevant for siblings who might become possible next gene therapy candidates. This pilot study included 115 subjects divided in three separate cohorts. Group 1 consisted of hospital personnel without known prior work exposure to rAAVrh74 (control group, 23 subjects). Group 2 were hospital-based personnel with known work exposure to rAAVrh74 (through pre-clinical and clinical studies, or direct contact with patient's specimen, 35 subjects) and Group 3 were relatives of patients receiving rAAVrh74 as part of a gene transfer trial (57 subjects). Enzyme-linked immunosorbent assay (ELISA)-based detection was used to identify anti-AAVrh74 total antibodies. Titers of 1:50 and 1:400 were reported, considering the range of titers used for enrollment in different trials. We found that parents of patients receiving gene transfer had a 3-fold greater risk of AAVrh74 seropositivity at 1:50 compared to the control group: 33.3% AAVrh74 positive (19/57 subjects) vs 13% negative (3/23 subjects), with a relative risk of 2.6%. Additionally, we observed that there were no statistically significant differences between two hospital personnel cohorts, non-exposed (Group 1) and exposed (Group 2), in terms of antibody positivity to AAVrh74. Finally, antibody titers at 1:400 were not different between Groups 1,2, or 3. These preliminary results serve as a caution to family members caring for children undergoing AAV gene transfer, warning that viral shedding following gene transfer can have an effect on the antibody titers. Prospective studies are on the way, with greater