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

Researchers have developed a new human transferrin receptor (TfR1)-binding AAV capsid called BI-TfR1 CapX, which can deliver genes more efficiently and safely throughout the central nervous system (CNS). In tests using adult humanized TFRC mice, BI-TfR1 CapX transduced more than 80% of cortical and spinal neurons, as well as around 60% of cortical astrocytes, using a low intravenous dose. This was compared to the AAV9 capsid, which had lower distribution and expression in several peripheral tissues.

What sets BI-TfR1 CapX apart is its rapid ability to cross the blood-brain barrier (BBB) and enter the brain tissue. The researchers observed that the CapX bound to the CNS vasculature within minutes, and a significant portion of its genetic material reached parenchymal nuclei within 24 hours. To demonstrate its potential, they delivered a Prnp-targeted epigenetic silencer called Prnp-CHARM via BI-TfR1 CapX.

This treatment successfully reduced brain Prnp mRNA by over 95%, which required 18 times fewer vector genomes per brain cell than using AAV-PHP.eB to achieve a 50% reduction in brain Prnp mRNA levels.

Moreover, BI-TfR1 CapX was used to deliver a dual-vector cytosine base editor that introduced a protein-truncating PRNP stop codon. This treatment lowered brain prion protein levels by 80%. These promising results suggest that BI-TfR1 CapX could be an attractive vehicle for human CNS gene therapy, overcoming the central obstacle of safely and effectively delivering genes to treat genetic diseases of the brain and spinal cord.