Type 2 diabetes (T2D) is a multi-organ damaging, debilitating and lethal disease on an epidemic scale. According to Center for Disease Control and Prevention, at least 54 million American adults had pre-diabetes and 23.6 million had diabetes. The obesity rates in the US have now reached 32.2% and 35.5% among adult men and women. Even more concerning, children with T2D are on the rise along with their rising obesity rates. Thus, T2D poses a grave threat to human health and an escalating burden to the health care system. Current therapies are far from ideal. They manage blood glucose but poorly address the causes and fail to stop the disease. We wish to use muscle as a platform for T2D gene therapy, since muscle is the largest organ in the body and a major site for insulin-mediated glucose homeostasis and energy consumption. Based on our encouraging preliminary studies, we will continue to use adeno-associated virus as the muscle gene delivery vector, myostatin propeptide and follistatin as the therapeutic genes, the commonly used leptin receptor defective T2D/obesity mice (db/db) as the animal model, to test our hypothesis that skeletal muscles can be an effective platform for T2D gene therapy. We will systematically evaluate and improve the therapeutic efficacies as well as safety profiles. We will also investigate potential molecular mechanisms that substantiate the clinical outcomes. The success of this proposal should lead to a new, effective and safe therapy for T2D.

Public Health Relevance

Type-2 diabetes afflicts tens of millions Americans. The costs to the society and specifically to the health care system are enormous (greater than $174 billion in 2007 according to data from CDC). This RO1 proposal plans to develop a gene therapy approach using diabetic and obese mouse as a model. The success of this proposal will lead to new ways and new drug candidates for the treatment of type 2 diabetes..

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK090380-01A1
Application #
8105547
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Mckeon, Catherine T
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$370,000
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hu, Jim; Xia, Emily; Yang, Leo et al. (2016) Gene editing: A new step and a new direction toward finding a cure for Duchenne muscular dystrophy (DMD). Genes Dis 3:101-102
Zhao, Chunxia; Qiao, Chunping; Tang, Ru-Hang et al. (2015) Overcoming Insulin Insufficiency by Forced Follistatin Expression in ?-cells of db/db Mice. Mol Ther 23:866-874
Qiao, Chunping; Wang, Chi-Hsien; Zhao, Chunxia et al. (2014) Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery. Mol Ther 22:1890-9
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
Yang, Lin; Xiao, Xiao (2013) Creation of a cardiotropic adeno-associated virus: the story of viral directed evolution. Virol J 10:50
Lee, Hannah H; O'Malley, Michael J; Friel, Nicole A et al. (2013) Persistence, localization, and external control of transgene expression after single injection of adeno-associated virus into injured joints. Hum Gene Ther 24:457-66
Qiao, Chunping; Yuan, Zhenhua; Li, Jianbin et al. (2012) Single tyrosine mutation in AAV8 and AAV9 capsids is insufficient to enhance gene delivery to skeletal muscle and heart. Hum Gene Ther Methods 23:29-37