Stable therapy in Pompe disease through genome editing

在庞贝氏症（酸性麦芽糖酶缺乏症; 糖原累积病II型），一种由酸性β-葡糖苷酶（GAA）引起的溶酶体累积病 导致溶酶体糖原积累和使人虚弱的缺乏症。患者 庞贝氏症接受延长生命的酶替代疗法（ERT），包括 重组人GAA;然而，ERT不能完全逆转包括糖原储存和 功能缺陷对ERT缺乏完全反应刺激了新疗法的发展， 包括基因治疗。基因治疗的发展在很大程度上忽视了早期治疗的必要性， 临床前研究我们建议解决庞贝氏症的基因治疗如何逆转 通过以下具体目标参与神经系统：1）翻译基因组编辑， 在生命早期，GAA在肝脏中的稳定储存库; 2）评估个性化基因组编辑用于治疗 Pompe病早期的生活。相比之下，开发庞贝氏症的基因治疗可能会带来好处。 包括骨骼肌的矫正和生活质量的提高。这些具体目标将 通过开发基因组编辑来解决庞贝氏症早期治疗的需求，这将指导 设计未来的临床试验，以开发高效的基因疗法。

The need for treatment early in life has emerged as an unmet need in Pompe disease (acid maltase deficiency; glycogen storage disease type II), a lysosomal storage disorder caused by acid -glucosidase (GAA) deficiency that leads to the accumulation of lysosomal glycogen and debilitating weakness. Patients with Pompe disease receive life-prolonging therapy with enzyme replacement therapy (ERT) consisting of recombinant human GAA; however, ERT fails to completely reverse symptoms including glycogen storage and functional deficits. The lack of a complete response to ERT has stimulated the development of new therapies, including gene therapy. Gene therapy development has largely overlooked the need for early treatment during preclinical research. We propose to address the question of how gene therapy for Pompe disease can reverse nervous system involvement through the following Specific Aims: 1) Translate genome editing that establishes a stable depot for GAA to the liver early in life; 2) Evaluate personalized genome editing for the treatment of Pompe disease early in life. Developing gene therapy in Pompe disease may provide benefits in comparison with ERT, including the correction of skeletal muscle and enhanced quality of life. These Specific Aims will address the need for treatment early in life in Pompe disease by developing genome editing, which will guide the design of future clinical trials to develop highly effective genetic therapy.