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An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.
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.
Affiliation
  • Huang Q; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Chan KY; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Wu J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Botticello-Romero NR; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Zheng Q; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Lou S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Keyes C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Svanbergsson A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Johnston J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Mills A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Lin CY; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Brauer PP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Clouse G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Pacouret S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Harvey JW; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Beddow T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Hurley JK; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Tobey IG; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Powell M; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Chen AT; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Barry AJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Eid FE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • Chan YA; Department of Systems and Computer Engineering, Faculty of Engineering, Al-Azhar University, Cairo 11651, Egypt.
  • Deverman BE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
Science ; 384(6701): 1220-1227, 2024 Jun 14.
Article in En | MEDLINE | ID: mdl-38753766
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 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Transferrin / Brain / Antigens, CD / Capsid / Gene Transfer Techniques / Genetic Vectors / Glucosylceramidase Limits: Animals / Humans Language: En Journal: Science Year: 2024 Document type: Article Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Transferrin / Brain / Antigens, CD / Capsid / Gene Transfer Techniques / Genetic Vectors / Glucosylceramidase Limits: Animals / Humans Language: En Journal: Science Year: 2024 Document type: Article Country of publication: