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

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) previ...

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Published in:Science advances 2023-04, Vol.9 (16), p.eadg6618-eadg6618
Main Authors: Shay, Timothy F, Sullivan, Erin E, Ding, Xiaozhe, Chen, Xinhong, Ravindra Kumar, Sripriya, Goertsen, David, Brown, David, Crosby, Anaya, Vielmetter, Jost, Borsos, Máté, Wolfe, Damien A, Lam, Annie W, Gradinaru, Viviana
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier - metabolism
Brain - metabolism
Carbonic Anhydrase IV - genetics
Carbonic Anhydrase IV - metabolism
Dependovirus - genetics
Dependovirus - metabolism
Gene Transfer Techniques
Humans
Mice
Neuroscience
Primates - genetics
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Summary: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 -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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adg6618