Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors

[ DOI: https://doi.org/10.35077/g.1146 ]

 

Dataset Citation:

Gradinaru, Viviana. (2023). Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors. [ Collection / Dataset ]. Brain Image Library. https://doi.org/10.35077/g.1146

 

Abstract:

The blood-brain barrier (BBB) presents a major challenge for delivering large molecules to study and treat the central nervous system. This is due in part to the scarcity of targets known to mediate BBB crossing. To identify novel targets, we leverage a panel of adeno-associated viruses (AAVs) previously identified through mechanism-agnostic directed evolution for improved BBB transcytosis. Screening potential cognate receptors for enhanced BBB crossing, we identify two targets: murine-restricted LY6C1 and widely conserved carbonic anhydrase IV (CA-IV). We apply AlphaFold-based in silico methods to generate capsid-receptor binding models to predict the affinity of AAVs for these identified receptors. Demonstrating how these tools can unlock target-focused engineering strategies, we create an enhanced LY6C1-binding vector, AAV-PHP.eC, that, unlike our prior PHP.eB, also works in Ly6a-deficient mouse strains such as BALB/cJ. Combined with structural insights from computational modeling, the identification of primate-conserved CA-IV enables the design of more specific and potent human brain–penetrant chemicals and biologicals, including gene delivery vectors.

 

Funding:

National Institutes of Health 1-UF1-MH128336-01 Engineered AAV Identification, Validation, and Dissemination Pipeline for Brain Cell Type-Specific Manipulation Across Species;
National Institutes of Health 5-DP1-NS111369-04 Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors;
National Institutes of Health 1-U24-MH131054-01 Broadening access with an Armamentarium Vector Core Powered by Inclusive Research Experiences;
California Institute of Technology NA Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER)

 

Contributors:

Gradinaru, Viviana (ProjectLeader) [ORCID: https://orcid.org/0000-0001-5868-348X ] California Institute of Technology

 

Related Identifiers:

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