Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease caused by the lack of dystrophin, which eventually leads to apoptosis of muscle cells and impaired muscle contractility. Induced pluripotent stem cells (iPSC) offer the potential to correct the DMD gene defect and create healthy cells for transplantation without causing immune activation. However, this requires engineering iPSCs to facilitate homing and engraftment into diseased muscle tissue without promoting tumorigenesis. Our long-term goal is to optimize the differentiation of iPSC into myogenic progenitor cells (MPC) that are directed to home into muscle tissue and engraft without undergoing unrestrained growth. Our central hypothesis is that precise MPC genetic engineering, coupled with targeted modification of the host muscle niche by preconditioning or exosome delivery, will boost homing and engraftment of donor iPSC-derived MPC via the SDF-CXCR4 axis to safely and effectively treat DMD. The rationale is to develop methodology to produce large quantities of functional MPC from patients with DMD that are tumor free and can effectively home to sites of muscle injury and facilitate repair. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims.
In Aim 1, we will test the hypothesis that iPSC-derived progenitor cells are effective and safe for regeneration of dystrophic muscle.
In Aim 2, we will test the hypothesis that activation of CXCR4 in iPSC-derived myogenic precursors from DMD mice using a CRISPR-on based genomic platform improves engraftment of donor cells in DMD mice.
In Aim 3, we will test the hypothesis that optimizing the regenerative microenvironment in muscle by ischemic preconditioning or iPSC-exosome-mediated delivery of SDF-1? protein enhances the homing and/or survival of donor MPC to augment muscle repair. These experiments have the potential to demonstrate that transplantation of iPSC-derived progenitors, coupled with methods to optimize the host muscle microenvironment, will more effectively ameliorate dystrophic pathology and improve the quality of life for patients with DMD.

Public Health Relevance

Duchenne Muscular Dystrophy is a genetic disease that causes progressive muscle weakness and death in young men. This proposal will establish novel methods for producing myogenic progenitors derived from integration-free induced pluripotent stem cells (iPSC), their mobilization, and engraftment into the dystrophic muscle for restoring normal muscle population.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02)S)
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Cheever, Thomas
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Augusta University
Internal Medicine/Medicine
Schools of Medicine
United States
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Zarzour, Abdalrahman; Kim, Ha Won; Weintraub, Neal L (2018) Understanding Obesity-Related Cardiovascular Disease: It's All About Balance. Circulation 138:64-66
Bayoumi, Ahmed S; Park, Kyoung-Mi; Wang, Yongchao et al. (2018) A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol 114:72-82
Aonuma, Tatsuya; Bayoumi, Ahmed S; Tang, Yaoliang et al. (2018) A circular RNA regulator quaking: a novel gold mine to be unfolded in doxorubicin-mediated cardiotoxicity. Noncoding RNA Investig 2:
Hagan, Mackenzie; Ashraf, Muhammad; Kim, Il-Man et al. (2018) Effective regeneration of dystrophic muscle using autologous iPSC-derived progenitors with CRISPR-Cas9 mediated precise correction. Med Hypotheses 110:97-100
Zhu, Jinyun; Lu, Kai; Zhang, Ning et al. (2018) Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol 46:1659-1670
Teoh, Jian-Peng; Bayoumi, Ahmed S; Aonuma, Tatsuya et al. (2018) ?-arrestin-biased agonism of ?-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225-236
Ruan, Xiao-Fen; Li, Yong-Jun; Ju, Cheng-Wei et al. (2018) Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. Acta Pharmacol Sin 39:579-586
Benson, Tyler W; Weintraub, Daniel S; Crowe, Matthew et al. (2018) Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol 473:79-88
Xuan, Wanling; Wang, Yan; Tang, Yaoliang et al. (2018) Cardiac Progenitors Induced from Human Induced Pluripotent Stem Cells with Cardiogenic Small Molecule Effectively Regenerate Infarcted Hearts and Attenuate Fibrosis. Shock 50:627-639
Bayoumi, Ahmed S; Aonuma, Tatsuya; Teoh, Jian-Peng et al. (2018) Circular noncoding RNAs as potential therapies and circulating biomarkers for cardiovascular diseases. Acta Pharmacol Sin 39:1100-1109

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