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An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery.
Huang, Qin; Chan, Ken Y; Lou, Shan; Keyes, Casey; Wu, Jason; Botticello-Romero, Nuria R; Zheng, Qingxia; Johnston, Jencilin; Mills, Allan; 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.
Afiliación
  • Huang Q; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Chan KY; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Lou S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Keyes C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Wu J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Botticello-Romero NR; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Zheng Q; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Johnston J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Mills A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Brauer PP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Clouse G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Pacouret S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Harvey JW; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Beddow T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Hurley JK; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Tobey IG; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Powell M; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Chen AT; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Barry AJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Eid FE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
  • Chan YA; Department of Systems and Computer Engineering, Faculty of Engineering, Al-Azhar University; Cairo, Egypt.
  • Deverman BE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
bioRxiv ; 2023 Dec 22.
Article en En | MEDLINE | ID: mdl-38187643
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 Parkinson's 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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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos