Structural characterization of antibody-responses following Zolgensma treatment for AAV capsid engineering to expand patient cohorts
Year: 2025
Type: article
Abstract: Monoclonal antibodies are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids that are used as gene therapy delivery vectors. The presence of pre-existing neutralizing antibodies in large portions of the human population poses a significant challenge for AAV-mediated gene therapy, primarily targeting the capsid leading to vector inactivation and loss of treatment efficacy. This study structurally characterizes the interactions of 21 human-derived neutralizing antibodies from three patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The antibodies bound to the 2-fold depression or the 3-fold protrusions do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with many antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with antibody escape phenotypes. These AAV9 capsid variants have the potential to expand the patient cohort to include those that were previously excluded due to their pre-existing neutralizing antibodies against the wtAAV9 capsid, and the possibly of further treatment to those requiring redosing.
Source: Nature Communications
Authors: Mario Mietzsch, Jane Hsi, Austin R. Nelson, Neeta Khandekar, Ann-Maree Huang, Nicholas JC Smith, Jon Zachary, Lindsay Potts, Michelle A. Farrar, Paul Chipman, Mohammad Ghanem, Ian E. Alexander, Grant J. Logan, Juha T. Huiskonen, Robert McKenna
Institutions: University of Florida, The University of Sydney, Children's Medical Research Institute, Sydney Children’s Hospitals Network, Women's and Children's Hospital, Women's and Children's Health Network, The University of Adelaide, UNSW Sydney, Sydney Children's Hospital, University of Helsinki, HiLIFE – Elämäntieteiden Instituutti
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Rebecca L. Cooper Medical Research Foundation, Academy of Finland, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, International Centre for Bamboo and Rattan, National Institute of General Medical Sciences, SLAC National Accelerator Laboratory, Common Fund
Awards: G1368189568, The Stanford-SLAC CryoEM Center, G2915379726, Chaperonin response to protein misfolding in neurodegenerative disease (ResponseHD), Structural studies of AAV capsids and their glycan receptor interactions, Improving the health outcomes for children with rare neurological diseases with genomic technologies, G6504665321, G6809074, Exploiting anti-capsid humoral immunity induced in infants receiving gene therapy for Spinal Muscular Atrophy to engineer the next generation of gene transfer vectors, G9000037672, G9000167582
OpenAlex ID: W4409596983