RNA Therapeutics Institute Publications

UMMS Affiliation

RNA Therapeutics Institute; Department of Neurology; Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Medicine

Publication Date


Document Type



Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics | Neuroscience and Neurobiology | Therapeutics


Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.

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Copyright © 2016 American Society of Gene and Cell Therapy. Under a Creative Commons license.

DOI of Published Version



Mol Ther. 2016 Apr;24(4):726-35. doi: 10.1038/mt.2015.231. Epub 2015 Dec 28. Link to article on publisher's site

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy


Full list of authors omitted for brevity. For full list see article.

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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.