Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation
Faculty Advisor
Miguel Sena-Esteves, Ph.D.Academic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
NeurologyDocument Type
Doctoral DissertationPublication Date
2016-01-07Keywords
Dissertations, UMMSGenetic Therapy
Genetic Vectors
Huntington Disease
Central Nervous System Diseases
Dependovirus
Genetic Therapy
Genetic Vectors
Huntington Disease
Central Nervous System DiseasesDependovirusGeneticsMolecular GeneticsNervous System DiseasesNeurologyTherapeutics
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Show full item recordAbstract
Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.DOI
10.13028/M2DS3XPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32178Rights
Copyright is held by the author, with all rights reserved.Scopus Count
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