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

Qin Huang; Ken Y. Chan; Jason Hongliu Wu; Nuria Roxana Botticello-Romero; Qingxia Zheng; Shan Lou; Casey Keyes; Alexander Svanbergsson; Jencilin Johnston; Allan Mills; C.-L. Lin; Pamela P. Brauer; Gabrielle Clouse; Simon Pacouret; John W. Harvey; Thomas Beddow; Jenna K. Hurley; Isabelle G. Tobey; Megan Powell; Albert Tian Chen; Andrew J. Barry; Fatma-Elzahraa Eid; Yujia A. Chan; Benjamin E. Deverman

doi:10.1126/science.adm8386

NeuroscienceScienceMay 16, 2024

Peer-reviewed journal article

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

Qin Huang iD, Ken Y. Chan iD, Jason Hongliu Wu iD, Nuria Roxana Botticello-Romero iD, Qingxia Zheng iD, Shan Lou iD, Casey Keyes iD, Alexander Svanbergsson iD, Jencilin Johnston, Allan Mills iD, C.-L. Lin iD, Pamela P. Brauer, Gabrielle Clouse, Simon Pacouret, John W. Harvey iD, Thomas Beddow, Jenna K. Hurley iD, Isabelle G. Tobey iD, Megan Powell, Albert Tian Chen iD, Andrew J. Barry iD, Fatma-Elzahraa Eid iD, Yujia A. Chan iD, Benjamin E. Deverman iD

Abstract

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in 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 Parkinsons disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.

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