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

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072176-05
Application #
8197174
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Park, Eun-Chung
Project Start
2007-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$358,366
Indirect Cost
$99,055
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hirsch, Matthew L; Wolf, Sonya J; Samulski, R J (2016) Delivering Transgenic DNA Exceeding the Carrying Capacity of AAV Vectors. Methods Mol Biol 1382:21-39
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Hirsch, M L (2015) Adeno-associated virus inverted terminal repeats stimulate gene editing. Gene Ther 22:190-5
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Hastie, Eric; Samulski, R Jude (2015) Recombinant adeno-associated virus vectors in the treatment of rare diseases. Expert Opin Orphan Drugs 3:675-689
Lentz, Thomas B; Samulski, R Jude (2015) Insight into the mechanism of inhibition of adeno-associated virus by the Mre11/Rad50/Nbs1 complex. J Virol 89:181-94

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