An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery

Area of Science:

• Neuroscience
• Genetics
• Biotechnology

Background:

• Developing effective gene delivery vehicles for the central nervous system (CNS) is crucial for treating genetic neurological disorders.
• The blood-brain barrier (BBB) presents a significant obstacle for delivering therapeutic agents to the brain.

Approach:

• Engineered a novel adeno-associated virus (AAV) capsid, named BI-hTFR1, designed to bind the human Transferrin Receptor (TfR1) expressed on the BBB.
• Demonstrated active transport of BI-hTFR1 across a human brain endothelial cell layer.
• Evaluated BI-hTFR1's in vivo performance in human TFRC knock-in mice.

Key Points:

• BI-hTFR1 exhibited significantly enhanced tropism for the CNS in human TFRC knock-in mice, showing 40-50 times greater reporter gene expression compared to AAV9.
• This enhanced CNS targeting was specific and not observed in wild-type mice.
• When used for GBA1 gene delivery, BI-hTFR1 significantly increased glucocerebrosidase activity in the brain and cerebrospinal fluid.

Conclusions:

• BI-hTFR1 demonstrates superior CNS gene delivery efficiency and specificity.
• This engineered AAV vector holds promise as a therapeutic tool for genetic diseases affecting the CNS, such as Gaucher and Parkinson's disease.