Our purpose is to study gene therapy in mouse models of Fukutin-related protein (FKRP) deficiency. FKRP is a glycotransferase, one of the key enzymes in the glycosylation pathway of ?-dystroglycan (?-DG). Alpha-DG is a membrane protein abundant in muscle and nerve. Mutations in FKRP gene cause a spectrum of muscular dystrophies. The most common form is limb girdle muscular dystrophy 2I (LGMD2I) that manifests cardiomyopathy at later stage. The rare and severe forms, including congenital muscular dystrophy (MDC1C), Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB), also show central nervous system (CNS) deficiency. No curative or effective treatment is clinically available for any muscular dystrophies. Our short-term goal is to use the new mouse models to study FKRP gene therapy efficacy and safety, with the long-term goal to develop an effective treatment for FKRP-related diseases. Since the vast majority of the FKRP-deficient patients suffer from LGMD2I, we design Aim 1 to focus on LGMD2I gene therapy, which will practically find and benefit many more patients. On the other hand, the severe and early-onset FKRP- related diseases are extremely rare but they affect young children with CNS complications. We therefore have Aim 2 dedicated to this type of diseases with an emphasis on CNS gene delivery. FKRP deficiency has been under-studied and its basic biochemistry is not as thoroughly understood as most of the well-defined classic enzymes. As a result, we put forth Aim 3 to further elucidate the in vivo functions of FKRP, to gain useful information and guidance for gene therapy.
Our purpose is to study gene therapy in mouse models of Fukutin-related protein (FKRP) deficiency. FKRP deficiency has been under-studied and its basic biochemistry is not as thoroughly understood as most of the well-defined classic enzymes. Our short-term goal is to use the new mouse models to study FKRP gene therapy efficacy and safety, with the long-term goal to develop an effective treatment for FKRP-related diseases.
|Zhao, Chunxia; Qiao, Chunping; Tang, Ru-Hang et al. (2015) Overcoming Insulin Insufficiency by Forced Follistatin Expression in Î²-cells of db/db Mice. Mol Ther 23:866-74|
|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|
|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|
|Xu, Lei; Lu, Pei Juan; Wang, Chi-Hsien et al. (2013) Adeno-associated virus 9 mediated FKRP gene therapy restores functional glycosylation of Î±-dystroglycan and improves muscle functions. Mol Ther 21:1832-40|
|Yang, Lin; Xiao, Xiao (2013) Creation of a cardiotropic adeno-associated virus: the story of viral directed evolution. Virol J 10:50|