An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery
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-br...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2024-06, Vol.384 (6701), p.1220-1227 |
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| creator | 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 |
| description | 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
knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver
, 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_str_mv | 10.1126/science.adm8386 |
| format | Article |
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knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver
, 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.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.adm8386</identifier><identifier>PMID: 38753766</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Animal models ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Brain - metabolism ; Capsid - metabolism ; Capsid Proteins - genetics ; Capsid Proteins - metabolism ; Central nervous system ; Dependovirus - genetics ; Endothelial Cells - metabolism ; Expression vectors ; Gaucher's disease ; Gene Knock-In Techniques ; Gene therapy ; Gene transfer ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors ; Humans ; Mice ; Proteins ; Receptors ; Receptors, Transferrin - genetics ; Receptors, Transferrin - metabolism ; Transferrin ; Transferrins ; Transgenic mice</subject><ispartof>Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6701), p.1220-1227</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c325t-3ed40fdf2c3499958dbec1d3842dce0b1166c2948050698dd07692ffbe6b970d3</citedby><cites>FETCH-LOGICAL-c325t-3ed40fdf2c3499958dbec1d3842dce0b1166c2948050698dd07692ffbe6b970d3</cites><orcidid>0000-0003-3056-7764 ; 0000-0002-7170-7455 ; 0000-0002-4667-679X ; 0009-0009-5866-177X ; 0000-0003-3036-9928 ; 0000-0002-1638-9917 ; 0000-0003-4435-7653 ; 0009-0005-4477-853X ; 0009-0009-9138-6853 ; 0000-0002-5387-0208 ; 0000-0002-0731-637X ; 0000-0001-5428-3809 ; 0000-0002-6223-9303 ; 0009-0004-3948-2307 ; 0000-0002-8853-5186 ; 0000-0001-8763-0221</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38753766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Qin</creatorcontrib><creatorcontrib>Chan, Ken Y</creatorcontrib><creatorcontrib>Wu, Jason</creatorcontrib><creatorcontrib>Botticello-Romero, Nuria R</creatorcontrib><creatorcontrib>Zheng, Qingxia</creatorcontrib><creatorcontrib>Lou, Shan</creatorcontrib><creatorcontrib>Keyes, Casey</creatorcontrib><creatorcontrib>Svanbergsson, Alexander</creatorcontrib><creatorcontrib>Johnston, Jencilin</creatorcontrib><creatorcontrib>Mills, Allan</creatorcontrib><creatorcontrib>Lin, Chin-Yen</creatorcontrib><creatorcontrib>Brauer, Pamela P</creatorcontrib><creatorcontrib>Clouse, Gabrielle</creatorcontrib><creatorcontrib>Pacouret, Simon</creatorcontrib><creatorcontrib>Harvey, John W</creatorcontrib><creatorcontrib>Beddow, Thomas</creatorcontrib><creatorcontrib>Hurley, Jenna K</creatorcontrib><creatorcontrib>Tobey, Isabelle G</creatorcontrib><creatorcontrib>Powell, Megan</creatorcontrib><creatorcontrib>Chen, Albert T</creatorcontrib><creatorcontrib>Barry, Andrew J</creatorcontrib><creatorcontrib>Eid, Fatma-Elzahraa</creatorcontrib><creatorcontrib>Chan, Yujia A</creatorcontrib><creatorcontrib>Deverman, Benjamin E</creatorcontrib><title>An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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
knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver
, 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.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain - metabolism</subject><subject>Capsid - metabolism</subject><subject>Capsid Proteins - genetics</subject><subject>Capsid Proteins - metabolism</subject><subject>Central nervous system</subject><subject>Dependovirus - genetics</subject><subject>Endothelial Cells - metabolism</subject><subject>Expression vectors</subject><subject>Gaucher's disease</subject><subject>Gene Knock-In Techniques</subject><subject>Gene therapy</subject><subject>Gene transfer</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Mice</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Transferrin - 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genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Brain - metabolism</topic><topic>Capsid - metabolism</topic><topic>Capsid Proteins - genetics</topic><topic>Capsid Proteins - metabolism</topic><topic>Central nervous system</topic><topic>Dependovirus - genetics</topic><topic>Endothelial Cells - metabolism</topic><topic>Expression vectors</topic><topic>Gaucher's disease</topic><topic>Gene Knock-In Techniques</topic><topic>Gene therapy</topic><topic>Gene transfer</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Mice</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors, Transferrin - genetics</topic><topic>Receptors, Transferrin - metabolism</topic><topic>Transferrin</topic><topic>Transferrins</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Qin</creatorcontrib><creatorcontrib>Chan, Ken Y</creatorcontrib><creatorcontrib>Wu, Jason</creatorcontrib><creatorcontrib>Botticello-Romero, Nuria R</creatorcontrib><creatorcontrib>Zheng, Qingxia</creatorcontrib><creatorcontrib>Lou, Shan</creatorcontrib><creatorcontrib>Keyes, Casey</creatorcontrib><creatorcontrib>Svanbergsson, Alexander</creatorcontrib><creatorcontrib>Johnston, Jencilin</creatorcontrib><creatorcontrib>Mills, Allan</creatorcontrib><creatorcontrib>Lin, Chin-Yen</creatorcontrib><creatorcontrib>Brauer, Pamela P</creatorcontrib><creatorcontrib>Clouse, Gabrielle</creatorcontrib><creatorcontrib>Pacouret, Simon</creatorcontrib><creatorcontrib>Harvey, John W</creatorcontrib><creatorcontrib>Beddow, Thomas</creatorcontrib><creatorcontrib>Hurley, Jenna K</creatorcontrib><creatorcontrib>Tobey, Isabelle G</creatorcontrib><creatorcontrib>Powell, Megan</creatorcontrib><creatorcontrib>Chen, Albert T</creatorcontrib><creatorcontrib>Barry, Andrew J</creatorcontrib><creatorcontrib>Eid, Fatma-Elzahraa</creatorcontrib><creatorcontrib>Chan, Yujia A</creatorcontrib><creatorcontrib>Deverman, Benjamin E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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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
knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver
, 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.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>38753766</pmid><doi>10.1126/science.adm8386</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-3056-7764</orcidid><orcidid>https://orcid.org/0000-0002-7170-7455</orcidid><orcidid>https://orcid.org/0000-0002-4667-679X</orcidid><orcidid>https://orcid.org/0009-0009-5866-177X</orcidid><orcidid>https://orcid.org/0000-0003-3036-9928</orcidid><orcidid>https://orcid.org/0000-0002-1638-9917</orcidid><orcidid>https://orcid.org/0000-0003-4435-7653</orcidid><orcidid>https://orcid.org/0009-0005-4477-853X</orcidid><orcidid>https://orcid.org/0009-0009-9138-6853</orcidid><orcidid>https://orcid.org/0000-0002-5387-0208</orcidid><orcidid>https://orcid.org/0000-0002-0731-637X</orcidid><orcidid>https://orcid.org/0000-0001-5428-3809</orcidid><orcidid>https://orcid.org/0000-0002-6223-9303</orcidid><orcidid>https://orcid.org/0009-0004-3948-2307</orcidid><orcidid>https://orcid.org/0000-0002-8853-5186</orcidid><orcidid>https://orcid.org/0000-0001-8763-0221</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6701), p.1220-1227 |
| issn | 0036-8075 1095-9203 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3056666241 |
| source | American Association for the Advancement of Science; MEDLINE |
| subjects | Animal models Animals Antigens, CD - genetics Antigens, CD - metabolism Blood-brain barrier Blood-Brain Barrier - metabolism Brain - metabolism Capsid - metabolism Capsid Proteins - genetics Capsid Proteins - metabolism Central nervous system Dependovirus - genetics Endothelial Cells - metabolism Expression vectors Gaucher's disease Gene Knock-In Techniques Gene therapy Gene transfer Gene Transfer Techniques Genetic Therapy Genetic Vectors Humans Mice Proteins Receptors Receptors, Transferrin - genetics Receptors, Transferrin - metabolism Transferrin Transferrins Transgenic mice |
| title | An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T12%3A32%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20AAV%20capsid%20reprogrammed%20to%20bind%20human%20transferrin%20receptor%20mediates%20brain-wide%20gene%20delivery&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Huang,%20Qin&rft.date=2024-06-14&rft.volume=384&rft.issue=6701&rft.spage=1220&rft.epage=1227&rft.pages=1220-1227&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.adm8386&rft_dat=%3Cproquest_cross%3E3056666241%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3067421329&rft_id=info:pmid/38753766&rfr_iscdi=true |