title: B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study.
abstract: Gene therapy strategies for congenital myopathies may require repeat administration of adeno-associated viral (AAV) vectors in response to several limitations inherent to the clinical design: 1) administration of doses below therapeutic efficacy in patients enrolled in early phase clinical trials; 2) progressive reduction of the therapeutic gene expression over time as a result of increasing muscle mass in patients treated at a young age; and 3) a possibly faster depletion of pathogenic myofibers in this patient population. Immune responses triggered by the first vector administration, and to subsequent ones, represent a major obstacle for successful gene transfer in young patient population. Anti-capsid and anti-transgene product related humoral and cell-mediated responses have been previously observed in all preclinical models and human subjects who received gene therapy or ERT treatment for congenital myopathies. Immune responses may result in reduced efficacy of the gene transfer over time and/or may preclude for the possibility of re-administration of the same vector. This study presents a case of Pompe patient dosed with an AAV1-GAA vector after receiving Rituximab and Sirolimus to modulate the immune responses. A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non-responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future. This observation is significant for future gene therapy studies and establishes a clinically relevant approach to blocking immune responses to AAV vectors.
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: M
authors.initials: M
authors.lastname: Corti
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Me
authors.initials: M
authors.lastname: Elder
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Dj
authors.initials: D
authors.lastname: Falk
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: L
authors.initials: L
authors.lastname: Lawson
authors.affiliation: Department of Physical Therapy, University of Florida.
authors.forename: Bk
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Medicine, Karolinska Institute, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Tj
authors.initials: T
authors.lastname: Conlon
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: N
authors.initials: N
authors.lastname: Clément
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: K
authors.initials: K
authors.lastname: Erger
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: E
authors.initials: E
authors.lastname: Lavassani
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Pa
authors.initials: P
authors.lastname: Doerfler
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Rw
authors.initials: R
authors.lastname: Herzog
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine.
authors.forename: Bj
authors.initials: B
authors.lastname: Byrne
keywords: AAV; Capsid antibody; Immunology; Pompe disease