Authors
Tyler C Moyer, Brett A Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey Thompson, Nilesh Pande, Mathieu E Nonnenmacher
Published in
Molecular therapy : the journal of the American Society of Gene Therapy. Volume 33. Issue 8. Pages 3902-3916. Aug 06, 2025. Epub May 08, 2025.
Abstract
Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered adeno-associated virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform to generate VCAP-102, an AAV9 variant with markedly increased brain tropism following intravenous delivery in both rodents and primates. Relative to AAV9, VCAP-102 demonstrates 20- to 400-fold increased gene transfer across multiple brain regions. We identify alkaline phosphatase (ALPL) as the primary receptor used by VCAP-102 to cross the BBB and demonstrate that direct binding of VCAP-102 to human ALPL can initiate receptor-mediated transcytosis in a cell barrier model. Our work identifies VCAP-102 as a cross-species CNS gene delivery vector with a strong potential for clinical translation and establishes ALPL as a brain delivery shuttle capable of efficient BBB transport to maximize CNS delivery of biotherapeutics.
PMID:
40340250
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.
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