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dc.contributor.authorWang, Dan
dc.contributor.authorLi, Shaoyong
dc.contributor.authorGessler, Dominic J.
dc.contributor.authorXie, Jun
dc.contributor.authorZhong, Li
dc.contributor.authorLi, Jia
dc.contributor.authorTran, Karen
dc.contributor.authorVan Vliet, Kim
dc.contributor.authorRen, Lingzhi
dc.contributor.authorSu, Qin
dc.contributor.authorHe, Ran
dc.contributor.authorGoetzmann, Jason E.
dc.contributor.authorFlotte, Terence R.
dc.contributor.authorAgbandje-McKenna, Mavis
dc.contributor.authorGao, Guangping
dc.date2022-08-11T08:09:50.000
dc.date.accessioned2022-08-23T16:45:06Z
dc.date.available2022-08-23T16:45:06Z
dc.date.issued2018-06-15
dc.date.submitted2018-05-30
dc.identifier.citation<p>Mol Ther Methods Clin Dev. 2018 Jun 15;9:234-246. doi: 10.1016/j.omtm.2018.03.004. eCollection 2018 Jun 15. <a href="https://doi.org/10.1016/j.omtm.2018.03.004">Link to article on publisher's site</a></p>
dc.identifier.issn2329-0501 (Linking)
dc.identifier.doi10.1016/j.omtm.2018.03.004
dc.identifier.pmid29766031
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40619
dc.description.abstractAdeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed gene therapy in a mouse model of a fatal pediatric leukodystrophy. In light of recent success with profiling diversified natural AAV capsid repertoires and the understanding of AAV capsid sequence-structure-function relationship, such a combinatory approach to AAV capsid development is expected to further improve vector targeting and expand the vector toolbox for therapeutic gene delivery.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29766031&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAAV capsid
dc.subjectCNS disease
dc.subjectadeno-associated virus
dc.subjectgene therapy
dc.subjecttissue detargeting
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetic Phenomena
dc.subjectGenetics and Genomics
dc.subjectMolecular Biology
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.subjectPediatrics
dc.subjectTherapeutics
dc.titleA Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates
dc.typeArticle
dc.source.journaltitleMolecular therapy. Methods and clinical development
dc.source.volume9
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4433&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3422
dc.identifier.contextkey12222313
refterms.dateFOA2022-08-23T16:45:06Z
html.description.abstract<p>Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed gene therapy in a mouse model of a fatal pediatric leukodystrophy. In light of recent success with profiling diversified natural AAV capsid repertoires and the understanding of AAV capsid sequence-structure-function relationship, such a combinatory approach to AAV capsid development is expected to further improve vector targeting and expand the vector toolbox for therapeutic gene delivery.</p>
dc.identifier.submissionpathoapubs/3422
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentViral Vector Core
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentLi Weibo Institute for Rare Diseases Research
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pages234-246


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Copyright 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).