Abstract

Gene therapy in golden retriever muscular dystrophy model This project will focus on the DMD dog model (GRMD) to investigate blood-vessel-mediated gene delivery of AAV vectors into the limbs and eventually the wholedody.
Specific Aim 1 is designed to compare regional gene delivery efficiency of arterial and venous methods in the limbs. Arterial delivery with pressure and/or with vessel dilators was investigated in early studies by a few labs. But more recent studies have switched to the pressurized intravenous delivery methods. However, a latest report revived the arterial method again, but without the use of any additional pressure and drugs. These methods have their pros and cons, but are never compared side-by-side.
In Aim 1 we propose to compare and optimize the regional AAV vector delivery methods in dog limbs.
Specific Aim 2 is designed to examine systemic gene delivery efficiency of AAV8 and AAV9 in dogs. Previously we and others have shown that new serotypes of AAV can achieve wholebody gene delivery by simple intravenous injection in mice and hamsters.
In Aim 2, we plan to explore both AAV8 and AAV9 for systemic gene delivery in the dogs. We will also examine any novel AAV vectors yielded by Project 2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR056953-05
Application #
8380615
Study Section
Special Emphasis Panel (ZAR1-KM-J)
Project Start
Project End
2014-02-28
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$344,147
Indirect Cost
$112,013

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Chai, Zheng; Samulski, R Jude; Li, Chengwen (2018) Nab Escaping AAV Mutants Isolated from Mouse Muscles. Bio Protoc 8:
Li, Chengwen; Wu, Shuqing; Albright, Blake et al. (2016) Development of Patient-specific AAV Vectors After Neutralizing Antibody Selection for Enhanced Muscle Gene Transfer. Mol Ther 24:53-65
Fan, Zheng; Kocis, Keith; Valley, Robert et al. (2015) High-Pressure Transvenous Perfusion of the Upper Extremity in Human Muscular Dystrophy: A Safety Study with 0.9% Saline. Hum Gene Ther 26:614-21
Fan, Zheng; Wang, Jiahui; Ahn, Mihye et al. (2014) Characteristics of magnetic resonance imaging biomarkers in a natural history study of golden retriever muscular dystrophy. Neuromuscul Disord 24:178-91
Qiao, Chunping; Li, Chengwen; Zhao, Chunxia et al. (2014) K137R mutation on adeno-associated viral capsids had minimal effect on enhancing gene delivery in vivo. Hum Gene Ther Methods 25:33-9
Powers, William J (2014) Intravenous thrombolysis of basilar artery thrombosis. Ann Neurol 75:456-7
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
Hirsch, Matthew L; Li, Chengwen; Bellon, Isabella et al. (2013) Oversized AAV transductifon is mediated via a DNA-PKcs-independent, Rad51C-dependent repair pathway. Mol Ther 21:2205-16
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
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

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