Science (New York, N.Y.) · 2024
An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.
СтатьяНазвание и аннотация: Перевод в очереди
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Huang Qin, Chan Ken Y, Wu Jason, Botticello-Romero Nuria R, Zheng Qingxia, Lou Shan, Keyes Casey, Svanbergsson Alexander, Johnston Jencilin, Mills Allan, Lin Chin-Yen, Brauer Pamela P, Clouse Gabrielle, Pacouret Simon, Harvey John W, Beddow Thomas, Hurley Jenna K, Tobey Isabelle G, Powell Megan, Chen Albert T, Barry Andrew J, Eid Fatma-Elzahraa, Chan Yujia A, Deverman Benjamin E
Аннотация
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.