Targeting PTEN to ameliorate muscular dystrophy in a mouse model

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Targeting PTEN to ameliorate muscular dystrophy in a mouse model Abstract Duchenne muscular dystrophy (DMD) is a debilitating and lethal disease due to degeneration and wasting of skeletal muscles that are key for motility and respiration. Patients eventually lose ambulation and mobility, and experience respiratory failure. Currently there is no cure for this disease. The proposed research aims to provide basic understanding of how PTEN protein might be involved in the pathogenesis of DMD and explore a new PTEN-targeting therapeutic strategy to treat DMD in a mouse model, the mdx mice. The applicant’s team has recently identified phosphatase and tensin homolog (PTEN) as a new regulator of myogenesis. PTEN is a phosphatase that counteracts the growth factor-mediated signaling that is critical for muscle growth and repair through activation of muscle stem cells (also called muscle satellite cells, MuSCs). Interestingly, we and others found that PTEN levels are very low in healthy adult muscles but elevated in skeletal muscles of DMD patients and animal models, suggesting that PTEN upregulation may contribute to disease progression. To confirm this, we show in preliminary studies that muscle-specific knockout of Pten gene ameliorates muscle pathology and restores muscle function in mdx mice. These exciting results confirm that inhibition of PTEN may be translated to treat DMD in humans. However, targeting PTEN and its signaling requires a thorough understanding of the cellular and molecular mechanisms underlying PTEN function in dystrophic muscle, which will be investigated in the first part of the proposed study. To further explore the translatability of this discovery, we tested in preliminary studies the effect of a pharmacological inhibitor of PTEN (namely VO-OHpic) in mdx mice. We showed that VO-OHpic robustly improves muscle health and function without obvious side effects. To further improve the safety of VO-OHpic in vivo, we generated a nanoparticle (NP)-mediated delivery system with which to deliver VO-OHpic specifically to muscle cells to achieve sustained drug release and limit side effects. In the second part of the proposed research, we will further optimize this prototype drug delivery system and examine its utility and safety in mdx mice. Upon completion of the study, we will have not only gained imperative insights into the pathological function of PTEN in dystrophic muscle, but also developed a novel drug delivery system for sustained pharmacological inhibition of PTEN specifically in the muscle to ameliorate muscle pathology and improve muscle function in a preclinical animal model. These results will establish a solid foundation for clinical translation of this promising therapeutic strategy to treat DMD in humans. The muscle-targeting NP drug delivery system may also be adapted to deliver other therapeutics to treat DMD or other degenerative diseases.