Abstract

Gene therapy in golden retriever muscular dystrophy modelThis project will focus on the DMD dog model (GRMD) to investigate blood-vessel-mediated gene delivery ofAAV vectors into the limbs and eventually the wholedody.
Specific Aim 1 is designed to compare regionalgene delivery efficiency of arterial and venous methods in the limbs. Arterial delivery with pressure and/orwith vessel dilators was investigated in early studies by a few labs. But more recent studies have switched tothe pressurized intravenous delivery methods. However, a latest report revived the arterial method again, butwithout the use of any additional pressure and drugs. These methods have their pros and cons, but arenever compared side-by-side.
In Aim 1 we propose to compare and optimize the regional AAV vectordelivery methods in dog limbs.
Specific Aim 2 is designed to examine systemic gene delivery efficiency ofAAV8 and AAV9 in dogs. Previously we and others have shown that new serotypes of AAV can achievewholebody gene delivery by simple intravenous injection in mice and hamsters.
In Aim 2, we plan to exploreboth AAV8 and AAV9 for systemic gene delivery in the dogs. We will also examine any novel AAV vectorsyielded 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 #
1U54AR056953-01
Application #
7535880
Study Section
Special Emphasis Panel (ZAR1-KM-J (M1))
Project Start
2008-09-05
Project End
2013-08-31
Budget Start
2008-09-05
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$349,687
Indirect Cost

  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
Asokan, Aravind; Samulski, R Jude (2013) An emerging adeno-associated viral vector pipeline for cardiac gene therapy. Hum Gene Ther 24:906-13
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
He, Yi; Weinberg, Marc S; Hirsch, Matt et al. (2013) Kinetics of adeno-associated virus serotype 2 (AAV2) and AAV8 capsid antigen presentation in vivo are identical. Hum Gene Ther 24:545-53

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