A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates
Gessler, Dominic J.
Van Vliet, Kim
Goetzmann, Jason E.
Flotte, Terence R.
UMass Chan AffiliationsDepartment of Pediatrics
Viral Vector Core
Department of Microbiology and Physiological Systems
Li Weibo Institute for Rare Diseases Research
Horae Gene Therapy Center
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Genetics and Genomics
Nervous System Diseases
Neuroscience and Neurobiology
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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.
Mol Ther Methods Clin Dev. 2018 Jun 15;9:234-246. doi: 10.1016/j.omtm.2018.03.004. eCollection 2018 Jun 15. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40619
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/).
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/).