BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS

Chan, K. Y.; Lin, C.-Y.; Huang, Q.; Pacouret, S.; Zheng, Q.; Harvey, J. W.; Brauer, P. P.; Johnston, J.; Serack, F.; Davis, J. R.; Kamath, N. G.; Jereb, S.; Sprague, D. A.; Svanbergsson, A.; Boucher, M.; Minikel, E. V.; Vallabh, S. M.; Deverman, B. E.

doi:10.64898/2026.09.23.753669

bioRxiv · 10.64898/2026.09.23.753669

BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS

Chan, K. Y.·Lin, C.-Y.·Huang, Q.·Pacouret, S.·Zheng, Q.·Harvey, J. W.·Brauer, P. P.·Johnston, J.·Serack, F.·Davis, J. R.·Kamath, N. G.·Jereb, S.·Sprague, D. A.·Svanbergsson, A.·Boucher, M.·Minikel, E. V.·Vallabh, S. M.·Deverman, B. E.

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Abstract

Safe, efficient gene delivery throughout the CNS remains a central obstacle to treating genetic diseases of the brain and spinal cord. We describe BI-TfR1 CapX, a human transferrin receptor (TfR1)-binding AAV capsid that, after a low intravenous dose in adult humanized TFRC mice, transduced more than 80% of cortical and spinal neurons and ~60% of cortical astrocytes, with reduced distribution and expression in several peripheral tissues relative to AAV9. Unlike other engineered BBB-crossing capsids, CapX bound the CNS vasculature within minutes and a large fraction of its genomes reached parenchymal nuclei within 24 hours. Delivering a Prnp-targeted epigenetic silencer (Prnp-CHARM), CapX reduced brain Prnp mRNA by over 95% requiring 18-fold fewer vector genomes per brain cell than AAV-PHP.eB for 50% lowering. A CapX delivered dual-vector cytosine base editor installed a protein-truncating PRNP stop codon lowering brain prion protein by 80%. These properties make CapX an attractive vehicle for human CNS gene therapy.

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Chan, K. Y., Lin, C.-Y., Huang, Q., Pacouret, S., Zheng, Q., Harvey, J. W., Brauer, P. P., Johnston, J., Serack, F., Davis, J. R., Kamath, N. G., Jereb, S., Sprague, D. A., Svanbergsson, A., Boucher, M., Minikel, E. V., Vallabh, S. M., Deverman, B. E.. 2026-09-29. BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS. https://doi.org/10.64898/2026.09.23.753669

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