Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier

Moyer, T. C.; Hoffman, B. A.; Chen, W.; Shah, I.; Ren, X.-Q.; Knox, T.; Liu, J.; Wang, W.; Li, J.; Khalid, H.; Kulkarni, A. S.; Egbuchulam, M.; Clement, J.; Bloedel, A.; Child, M. A.; Kaur, R.; Rouse, E.; Graham, K.; Maura, D.; Thorpe, Z.; Sayed-Zahid, A.; Chung, C. H.-Y.; Kutchin, A.; Johnson, A.; Yao, J.; Thompson, J.; Pande, N.; Nonnenmacher, M. E.

doi:10.1101/2024.03.12.584703

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bioRxiv · 10.1101/2024.03.12.584703

Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier

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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. VCAP-102 demonstrates a similar CNS tropism in cynomolgus macaque, african green monkey, marmoset and mouse, showing 20- to 400-fold increased transgene expression across multiple brain regions relative to AAV9. We demonstrate that the enhanced CNS tropism of VCAP-102 results from direct interaction with alkaline phosphatase (ALPL), a highly conserved membrane-associated protein expressed on the brain vasculature. VCAP-102 interacts with human, primate and murine ALPL isoforms, and ectopic expression of ALPL is sufficient to initiate receptor-mediated transcytosis of VCAP-102 in an in vitro transwell 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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Moyer, T. C., Hoffman, B. A., Chen, W., Shah, I., Ren, X.-Q., Knox, T., Liu, J., Wang, W., Li, J., Khalid, H., Kulkarni, A. S., Egbuchulam, M., Clement, J., Bloedel, A., Child, M. A., Kaur, R., Rouse, E., Graham, K., Maura, D., Thorpe, Z., Sayed-Zahid, A., Chung, C. H.-Y., Kutchin, A., Johnson, A., Yao, J., Thompson, J., Pande, N., Nonnenmacher, M. E.. 2024-03-14. Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier. https://doi.org/10.1101/2024.03.12.584703

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