ArticleMolecular therapy : the journal of the American Society of Gene Therapy2025
Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it.
- AAV Gene Therapy Drug Development and Translation of Engineered Ocular and Neurotropic Capsids: A Systematic Review Using Natural Language Processing.Clinical and translational science · 2025Pooled it
- Gene therapy for hereditary hematological disorders: From clinical breakthroughs to future horizons.Molecular therapy. Nucleic acids · 2026Review
- Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.Molecular therapy. Advances · 2026Article
- Systematic evaluation of BBB-penetrant AAV capsids in marmosets identifies VCAP-102 as a highly efficient brain-transducing capsid.Molecular therapy. Advances · 2026Article
- Breaking Biological Barriers: Engineering Nanocarriers for Efficient Drug and Gene Delivery through Nano-Bio Interfaces and Biophysical Design.Applied physics reviews · 2026Article
- Recent advancements in improving cross-species applicability of bioengineered AAV capsids.Gene therapy · 2026Review
- CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics.Nature chemical biology · 2026Article
- Epigenetic editing approaches maturity: AI-driven precision design, delivery innovation, and the road to clinical translation.Clinical epigenetics · 2026Review
- Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Viral Infections and Neurodegenerative Diseases: Reinterpreting the Crosstalk Through a Dual-Role Lens.Current microbiology · 2026Review
- Optimized AAV vector enables potent therapeutic rescue of inherited glycosylphosphatidylinositol deficiency in mice.Molecular therapy. Advances · 2026Article
- Plant viruses as next-generation vectors for transgene-free genome editing, gene regulation, and rapid crop improvement.Plant molecular biology · 2026Review
- Transport pathways across the blood-brain barrier for waste clearance and drug delivery.Fluids and barriers of the CNS · 2026Review
- Recent Developments in Lipid Nanoparticle-Mediated Delivery of Biotherapeutics and Gene Therapy Across the Blood-Brain Barrier.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- CHARIOT-AAV: Conjugation of diverse vectors to adeno-associated viruses for delivery of large genes.bioRxiv : the preprint server for biology · 2026Article
- Improvement of Adeno-Associated Virus (AAV)-Based Technologies by Cell-Penetrating Penta-Peptides (CPP5s).Pharmaceutics · 2026Review
- Brain Endothelial Glycocalyx as a Blood-Facing Translational Interface in Alzheimer's Disease: Beyond "Leaky" Barriers Toward Repair-First Stratification.Drug design, development and therapy · 2026Review
- The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases.Frontiers in neuroscience · 2026Review
- Species barriers in AAV tropism: mechanisms, models, and emerging solutions for clinical translation.Acta biochimica Polonica · 2026Review
- Article
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Authors and funding
28 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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