UMMS Affiliation

Horae Gene Therapy Center; Li Weibo Institute for Rare Diseases Research; Department of Microbiology and Physiological Systems; Viral Vector Core; Department of Pediatrics

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Nervous System Diseases | Neuroscience and Neurobiology | Pediatrics | Therapeutics


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.


AAV capsid, CNS disease, adeno-associated virus, gene therapy, tissue detargeting

Rights and Permissions

Copyright 2018 The Authors. This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



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

Journal/Book/Conference Title

Molecular therapy. Methods and clinical development

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.



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