the gene therapy community with a versatile toolkit of AAV vectors. Our goal is to establish a thorough understanding of the structure-function correlates of the diverse tissue tropisms of AAV serotypes. To achieve such, we have devised a comprehensive, two- pronged approach to unravel structural attributes of AAV1-9, while simultaneously exploiting these serotypes as "blueprints" for novel AAV vector design. The approach exploits the ability of DNA shuffling to rapidly evolve novel phenotypes derived from parental serotypes followed by rational manipulation of novel AAV mutants to establish structural attributes at the amino acid level. The first strategy involves generation of a combinatorial AAV library through DNA shuffling of AAV serotype capsid sequences followed by directed evolution of cell type/receptor-specific mutants. The objective of this approach is to eliminate bias in the identification of so- called "hot spots" on the AAV capsid that impart a specific phenotype. The second approach is concerned with rational manipulation of such specific regions on AAV serotype capsids using

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Park, Eun-Chung
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Nicolson, Sarah C; Samulski, R Jude (2014) Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus. J Virol 88:4132-44
Bartus, Raymond T; Weinberg, Marc S; Samulski, R Jude (2014) Parkinson's disease gene therapy: success by design meets failure by efficacy. Mol Ther 22:487-97
Hirsch, Matthew L; Samulski, R Jude (2014) AAV-mediated gene editing via double-strand break repair. Methods Mol Biol 1114:291-307
Weinberg, Marc S; Nicolson, Sarah; Bhatt, Aadra P et al. (2014) Recombinant adeno-associated virus utilizes cell-specific infectious entry mechanisms. J Virol 88:12472-84
Hemphill, Daniel D; McIlwraith, C Wayne; Samulski, R Jude et al. (2014) Adeno-associated viral vectors show serotype specific transduction of equine joint tissue explants and cultured monolayers. Sci Rep 4:5861
Mitchell, Angela M; Hirsch, Matthew L; Li, Chengwen et al. (2014) Promyelocytic leukemia protein is a cell-intrinsic factor inhibiting parvovirus DNA replication. J Virol 88:925-36
Gray, S J; Nagabhushan Kalburgi, S; McCown, T J et al. (2013) Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 20:450-9
Ferreira, J R; Hirsch, M L; Zhang, L et al. (2013) Three-dimensional multipotent progenitor cell aggregates for expansion, osteogenic differentiation and 'in vivo' tracing with AAV vector serotype 6. Gene Ther 20:158-68
Asokan, Aravind; Samulski, R Jude (2013) An emerging adeno-associated viral vector pipeline for cardiac gene therapy. Hum Gene Ther 24:906-13
Mitchell, Angela M; Li, Chengwen; Samulski, R Jude (2013) Arsenic trioxide stabilizes accumulations of adeno-associated virus virions at the perinuclear region, increasing transduction in vitro and in vivo. J Virol 87:4571-83

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