Abstract
Adeno-associated virus (AAV)-based gene therapies are emerging strategies in Duchenne muscular dystrophy (DMD) treatment. Exposure to wild-type AAV can lead to development of neutralizing antibodies (NAbs) and blocking of AAV transduction, thereby limiting the delivery of AAV vector-based gene therapy. Therefore, it is imperative to check for the presence of AAV NAbs in a patient who is a candidate for gene therapy. We prospectively enrolled 101 genetically confirmed males with DMD (median age 11 years, 48% ambulatory and 59% on steroids) and performed AAV neutralization assays against AAV2, AAV8, AAV9, and AAVrh74 serotypes. The serotype analysis showed that AAV9 (36%) and AAVrh74 (32%) seroprevalence was lower compared with AAV2 (56%) and AAV8 (47%). Interestingly, age was not correlated with NAb titer for any of the capsids. NAb responses were observed at a higher frequency in African American participants and at a lower frequency in Caucasian participants for all four serotypes. Further analysis showed no significant differences in NAb titers regardless of serotype and whether participants were taking steroids or not. Finally, we observed higher AAV8, AAV9, and AAVrh74 seroprevalence and significantly higher AAV2 and AAV8 NAb titers in participants who were ambulatory compared with nonambulatory participants. Overall, these data identify AAV9 and AAVrh74 as the two serotypes with lower pre-existing NAb titers in this study's cohort of 101 males with DMD, possibly showing their utility in future gene therapy applications in treatment of this cohort of patients with DMD.