Characterization of the Serpentine Adeno-Associated Virus (SAAV) Capsid Structure: Receptor Interactions and Antigenicity
Mario Mietzsch, Joshua A. Hull, Victoria Makal, Alberto Jimenez Ybargollin, Jennifer C. Yu, Kedrick McKissock, Antonette Bennett, Judit J. Pénzes, Bridget Lins-Austin, Qian Yu, Paul R. Chipman, Nilakshee Bhattacharya, Duncan Sousa, David Strugatsky, Peter Tijssen, Robert McKenna, Mavis Agbandje‐McKenna
Abstract
AAVs are widely studied therapeutic gene delivery vectors. However, preexisting antibodies and their detrimental effect on therapeutic efficacy are a primary challenge encountered during clinical trials. In order to circumvent preexisting neutralizing antibodies targeting mammalian AAV capsids, serpentine AAV (SAAV) was evaluated as a potential alternative to existing mammalian therapeutic vectors. The SAAV capsid was found to be thermostable at a wide range of environmental pH conditions, and its structure showed conservation of the core capsid topology but displays high structural variability on the surface. At the same time, it binds to a common receptor, sialic acid, that is also utilized by other AAVs already being utilized in gene therapy trials. Contrary to the initial hypothesis, SAAV capsids were recognized by one in four human sera tested, pointing to conserved amino acids around the 5-fold region as epitopes for cross-reacting antibodies.