An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.

1. Science. 2024 Jun 14;384(6701):1220-1227. doi: 10.1126/science.adm8386. Epub 2024 May 16. An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Huang Q(#)(1), Chan KY(#)(1), Wu J(1), Botticello-Romero NR(1), Zheng Q(1), Lou S(1), Keyes C(1), Svanbergsson A(1), Johnston J(1), Mills A(1), Lin CY(1), Brauer PP(1), Clouse G(1), Pacouret S(1), Harvey JW(1), Beddow T(1), Hurley JK(1), Tobey IG(1), Powell M(1), Chen AT(1), Barry AJ(1), Eid FE(1)(2), Chan YA(1), Deverman BE(1). Author information: (1)Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA. (2)Department of Systems and Computer Engineering, Faculty of Engineering, Al-Azhar University, Cairo 11651, Egypt. (#)Contributed equally Update of bioRxiv. 2023 Dec 22:2023.12.20.572615. doi: 10.1101/2023.12.20.572615. Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of human TFRC knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy. DOI: 10.1126/science.adm8386 PMID: 38753766 [Indexed for MEDLINE]