Congenital muscular dystrophy (CMD) is a class of currently untreatable, severe genetic neuromuscular disorders affecting muscle as well as the central nervous system (CNS). The laminin-?2(merosin)-deficient congenital muscular dystrophy (MDC1A) is the most common of them, afflicts 4 in 500,000 children and causes premature death. The purpose of this proposal is to develop an efficient and non-invasive gene delivery method to cross the blood brain barrier (BBB) to the CNS, in addition to the muscle and heart. The method will be tested in a laminin ?2-knockout dyw/dyw mouse model with a mini-agrin gene to replace the lost functions of laminin ?2. Previously we showed that systemic AAV1-mini-agrin delivery greatly improved muscle pathology and extended their lifespan but it failed to deliver to the CNS for improvement of neurological pathology. Recently we found that transient hypothermia greatly enhances AAV delivery into the spinal cord and brain. We have also engineered new chimeric mini-agrin genes with broadened binding substrates and higher affinities. While further optimizing the technology, we propose to use the new enabling tools to test our general hypothesis that revamped mini-agrin gene delivery to muscle, heart and CNS will provide: 1) better and broader therapeutic benefits for muscle and nerve pathologies;and 2) greater improvement in physiological functions and lifespan of the dyw/dyw mouse model. The success of this research plan could be potentially translatable to MDC1A patients and to other neuromuscular diseases as well.
Congenital muscular dystrophy (CMD) is a class of currently untreatable, severe genetic neuromuscular disorders affecting muscle as well as the central nervous system (CNS). The laminin-?2(merosin)-deficient congenital muscular dystrophy (MDC1A) afflicts 4 in 500,000 children and causes premature death. This proposal is to develop an efficient and non-invasive method to delivery therapeutic genes to the muscle, heart spinal cord and brain. We will use the new method to test a revamped mini-agrin gene to treat a MDC1A mouse model. The success of this research plan could be potentially translatable to MDC1A patients and to other neuromuscular diseases as well.
|Bulaklak, Karen; Xiao, Bin; Qiao, Chunping et al. (2018) MicroRNA-206 Downregulation Improves Therapeutic Gene Expression and Motor Function in mdx Mice. Mol Ther Nucleic Acids 12:283-293|
|Jin, Quan; Qiao, Chunping; Li, Jianbin et al. (2018) Neonatal Systemic AAV-Mediated Gene Delivery of GDF11 Inhibits Skeletal Muscle Growth. Mol Ther 26:1109-1117|
|Qiao, Chunping; Dai, Yi; Nikolova, Viktoriya D et al. (2018) Amelioration of Muscle and Nerve Pathology in LAMA2 Muscular Dystrophy by AAV9-Mini-Agrin. Mol Ther Methods Clin Dev 9:47-56|
|Zheng, Hui; Qiao, Chunping; Tang, Ruhang et al. (2017) Follistatin N terminus differentially regulates muscle size and fat in vivo. Exp Mol Med 49:e377|
|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|