Structural dynamics insights into principles underlying the fitness of new broadly potent AAVs
Year: 2026
Type: preprint
Abstract: Adeno-associated virus (AAV) is a leading platform for gene therapy, but current clinical-stage vectors require high doses associated with adverse events. Engineering of AAVs has produced more efficient vectors, although the mechanism underlying these improvements often remains poorly understood, limiting further development and raising potential safety concerns. Here, we leveraged a new workflow for AAV engineering with single-cell resolution, called scAAVengr-Hunt, to create best-in-class AAVs for gene delivery. ATX002, the top-performing vector, demonstrates broad potency across species, including nonhuman primate, mouse, and human, as well as across retina and brain. To understand the mechanism underlying this broad potency, we performed molecular dynamics simulations comparing AAV variants spanning a range of fitness levels. Structural dynamics analysis revealed a bifunctional molecular mechanism that confers potency through increased affinity of the capsid to the AAV receptor and regulation of heparan sulfate binding. This work provides critical insights relating structural mechanism to the fitness of engineered AAVs and establishes rich new avenues for AAV engineering through the integration of sequence-level analysis with computational biophysics.
Authors: Molly E. Johnson, Bilge E. Ozturk, Thomas H. Tugwell, Maryl Lambros, Haley N. Janowitz, Keevon Flohr, Morgan Sedorovitz, Laura Campello, Jane E. Hartung, Brett Hogle, Megan Gillespie, Hannah Schriever, Hamzah Aweidah, Janis Koester, Inga Clausen, Stefan Seeber, Franco Revelant, Richard Schreurs, Fabian Koechl, Paul A. Sieving, José-Alain Sahel, William R. Stauffer, Rui T. Peixoto, Sascha Fauser, Rob Lin, James F. Conway, Susana da Silva, Jacek Krol, Miguel Betegon, Leah C. Byrne
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Direct electron detecting (DED) camera, High-Throughput Computing for Genomics and Bioinformatics Research, Cell type specific AAVs to study reward and cognition, A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types, Cryo-electron microscope, Core Grant for Vision Research, Role of retinoic acid signaling in fovea development
OpenAlex ID: W7140584770