There is good evidence that gene therapy may be an effective new way to treat muscular dystrophy. However, the :echnologies and information required to bring these therapies into standard medical practice remain to be developed. The goal of this proposal is to provide the Wellstone program with a Scientific Research Resource Core that will facilitate the rapid and safe delivery of clinical studies that will establish gene therapies value for the treatment of muscular dystrophy. One of the keys to rapidly bringing new research developments into the clinic is to effectively manage the flow of information and technologies during translational research. Numerous pitfalls, delays, and unanticipated problems are encountered during translational research, and without effective methods of avoiding them, progress is significantly slowed and becomes much more costly. For example, without effective technology management, the drug development process is slowed when the technology transitions from the basic research lab into early Process Development and scale-up for safety testing. Likewise, effective information management is crucial to quickly transition from the minimally-regulated, research environment into the highly regulated processes of drug manufacturing, safety testing, and clinical trials. Effective information management is also important in speeding the regulatory approval process through a range of Local and Federal agencies. Lastly, the technology and information must integrate into a clinical study for actual patient treatments to begin. Ineffective information and technology management at any of these transition points can endanger patient safety and significantly delay the entire drug development process. The UNC Joint Vector Laboratories are structured and organized so as to streamline the flow of technologies and drug development information. Our previous experiences in vector design, development, and production have allowed us to develop new organizational and operational paradigms. These new paradigms have a proven record of effectiveness as shown by our success in getting a Phase I study for Duchene's Muscular Dystrophy into clinical trials safely and within a very short period of time. Through this experience, and others, we have found that the key requirements are: 1) The ability to manufacture vectors in an efficient and cost effective manner, 2) Having standardized procedures in place for coordinating the activities of the investigator, the trial Sponsor, the drug manufacturer, and the various testing sites, 3) Having the expertise to make sure that the vectors used for pre-clinical and clinical studies meet specific standards of biologic quality (viral liter, infectivity, and purity), 4) Having the expertise to make sure the vectors used for pre-clinical and clinical studies meet the required drug safety standards and specifications, and 5) Having the regulatory expertise to be able to provide investigators with information and guidance so they can rapidly meet all regulatory expectations and can submit successful IND applications on their first attempt. In this proposal we outline the facilities, programs, and processes that we have created that have allowed us to rapidly develop clinical protocols. These are the procedures that we routinely now use to streamline the translational process and to ensure product and patient safety. In addition, we describe how we have integrated the manufacturing processes for the different stages of translational research and how we use this approach to provide investigators with a comprehensive assortment of research resources that they can use throughout the development of their research program. In the Preliminary Studies section, we describe how we have applied these technologies and quality contra programs to previous production campaigns for DMD. We also discuss new programs that we are currently developing that are designed to further enhance our ability to speed the drug development, manufacturing, and testing processes In the Research Design section we describe how we plan to provide these various technologies, information systems and drug development programs to MD investigators who will use our facilities as a Scientific Research Resource Core.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAR1-KM-J)
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University of North Carolina Chapel Hill
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United States
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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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