Structural characterization of antibody-responses following Zolgensma treatment for AAV capsid engineering to expand patient cohorts
Date
2025
Authors
Mietzsch, M.
Hsi, J.
Nelson, A.R.
Khandekar, N.
Huang, A.-M.
Smith, N.J.
Zachary, J.
Potts, L.
Farrar, M.A.
Chipman, P.
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Journal article
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Nature Communications, 2025; 16(1):3731-1-3731-15
Statement of Responsibility
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
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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.
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.