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.
Show 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.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids 96%
- Administration of barcoded AAV capsid library to the putamen of non-human primates identifies variants with efficient retrograde transport 95%
- Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion 94%
Similar papers in this journal
- Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates 95%
- Engineering Viral Vectors for Acoustically Targeted Gene Delivery 95%
- Precision Cas9 Genome Editing in vivo with All-in-one, Self-targeting AAV Vectors 94%
Similar papers in this journal
- Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids 95%
- Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans 94%
- Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons 92%
Similar papers in this journal
- AAVone: A Cost-Effective, Single-Plasmid Solution for Efficient AAV Production with Reduced DNA Impurities 92%
- Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing 91%
- Atrophin-1 Antisense Oligonucleotide Provides Robust Protection from Pathology in a Fully Humanized DRPLA Model 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.