Targeting PTEN to ameliorate muscular dystrophy in a mouse model

靶向PTEN改善小鼠模型中的肌营养不良症 摘要 杜氏肌营养不良症（DMD）是一种衰弱和致命的疾病，由于变性和浪费的肌肉萎缩症， 骨骼肌是运动和呼吸的关键。患者最终会失去行动能力和活动能力， 呼吸衰竭。目前，这种疾病没有治愈方法。拟议的研究旨在 为PTEN蛋白如何参与DMD的发病机制提供了基本的理解，并探索了一种新的治疗方法。 一种新的靶向PTEN的治疗策略，用于治疗小鼠模型mdx小鼠中的DMD。申请人团队 最近鉴定出磷酸酶和张力蛋白同源物（PTEN）作为肌生成的新调节剂。PTEN是一种 一种磷酸酶，可抵消对肌肉生长和修复至关重要的生长因子介导的信号 通过激活肌肉干细胞（也称为肌肉卫星细胞，MuSC）。有趣的是，我们和其他人 发现健康成人肌肉中的PTEN水平非常低，但DMD患者骨骼肌中的PTEN水平升高 和动物模型，提示PTEN上调可能有助于疾病进展。为了证实这一点， 我们在初步研究中表明，肌肉特异性敲除Pten基因可改善肌肉病理， 恢复mdx小鼠的肌肉功能。这些令人兴奋的结果证实，抑制PTEN可能被翻译为 来治疗人类的DMD然而，靶向PTEN及其信号传导需要彻底了解其作用机制。 在营养不良的肌肉中，PTEN功能的细胞和分子机制将被研究 在拟议研究的第一部分。为了进一步探索这一发现的可翻译性，我们在 初步研究了PTEN的药理学抑制剂（即VO-OHpic）在mdx小鼠中的作用。我们 研究表明，VO-OHpic可显著改善肌肉健康和功能，且无明显副作用。进一步 为了提高VO-OHpic在体内的安全性，我们制备了一种纳米颗粒（NP）介导的递送系统， 其将VO-OHpic特异性地递送到肌肉细胞，以实现持续的药物释放并限制副作用。 在拟议研究的第二部分，我们将进一步优化这一原型药物输送系统， 检查其在mdx小鼠中的效用和安全性。研究完成后，我们不仅可以获得 迫切需要深入了解PTEN在营养不良肌肉中的病理功能，而且还开发了一种新的 用于持续药理学抑制肌肉中特异性的PTEN以改善 肌肉病理学和改善肌肉功能。这些结果将建立一个 为临床转化这种有前途的治疗策略治疗人类DMD奠定了坚实的基础。的 肌肉靶向NP药物递送系统也可适于递送其它治疗剂以治疗DMD或 其他退行性疾病。

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.