BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS
- 1Broad Institute of MIT and Harvard
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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BibTeX
@misc{chan2026bitfr1,
title = {{BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS}},
author = {K. Y. Chan and C.-Y. Lin and Q. Huang and S. Pacouret and Q. Zheng and J. W. Harvey and P. P. Brauer and J. Johnston and F. Serack and J. R. Davis and N. G. Kamath and S. Jereb and D. A. Sprague and A. Svanbergsson and M. Boucher and E. V. Minikel and S. M. Vallabh and B. E. Deverman},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753669},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753669v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - BI-TfR1 CapX rapidly transits the blood-brain barrier for efficient, low-dose gene delivery throughout the CNS
AU - K. Y. Chan
AU - C.-Y. Lin
AU - Q. Huang
AU - S. Pacouret
AU - Q. Zheng
AU - J. W. Harvey
AU - P. P. Brauer
AU - J. Johnston
AU - F. Serack
AU - J. R. Davis
AU - N. G. Kamath
AU - S. Jereb
AU - D. A. Sprague
AU - A. Svanbergsson
AU - M. Boucher
AU - E. V. Minikel
AU - S. M. Vallabh
AU - B. E. Deverman
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753669
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753669v1
AB - 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.
ER -