Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations

Jerry R Mendell; Anne M Connolly; Kelly J Lehman; Danielle A Griffin; Sohrab Z Khan; Sachi D Dharia; Lucía Quintana-Gallardo; Louise R Rodino-Klapac

doi:10.1016/j.omtm.2022.02.011

Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations

Mol Ther Methods Clin Dev. 2022 Feb 26:25:74-83. doi: 10.1016/j.omtm.2022.02.011. eCollection 2022 Jun 9.

Authors

Affiliations

¹ Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
² Department of Pediatrics and Neurology, The Ohio State University, Columbus, OH 43205, USA.
³ Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142, USA.

Abstract

Given the increasing number of gene transfer therapy studies either completed or underway, there is growing attention to the importance of preexisting adaptive immunity to the viral vectors used. The recombinant viral vectors developed for gene transfer therapy share structural features with naturally occurring wild-type virus. Antibodies generated against viral vectors obtained through a previous exposure to wild-type virus can potentially compromise transgene expression by blocking transduction, thereby limiting the therapeutic efficacy of the gene transfer therapy; they may also pose potential safety concerns. Therefore, systemic gene transfer delivery requires testing patients for preexisting antibodies. Two different assays have been used: (1) binding assays that focus on total antibodies (both neutralizing and non-neutralizing) and (2) neutralizing assays that detect neutralizing antibodies. In this review we focus on adeno-associated virus-based gene therapies, describing the immune response that occurs to naturally occurring adeno-associated viruses, the implications for patients with this exposure, the assays used to detect preexisting immune responses, and strategies to circumvent preexisting adaptive immunity to expand the patient base that could benefit from such therapies.

Keywords: adeno-associated virus; antibodies; assays; binding assays; efficacy; gene transfer therapy; immunity; neutralizing assays; safety; titer.

Publication types

Review