Stable therapy in Pompe disease through genome editing

生命早期的治疗需求已经成为庞贝病(酸性麦芽糖酶缺乏症； 糖原储存病II型)，一种由酸性-葡萄糖苷酶(GaA)引起的溶酶体储存障碍 缺乏，导致溶酶体糖原积聚和虚弱。患有疾病的患者 庞贝病接受酶替代疗法(ERT)的延长生命治疗，该疗法包括 重组人GAA；然而，ERT未能完全逆转包括糖原储存和 功能缺陷。对ERT缺乏完全的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。我们建议解决庞培病的基因治疗如何逆转这一问题 神经系统通过以下具体目标参与：1)翻译基因组编辑，建立 在生命早期将GAA稳定地储存到肝脏；2)评估个性化基因组编辑治疗 早年的庞贝病。相比之下，开发庞培病的基因疗法可能会带来好处 通过ERT，包括矫正骨骼肌和提高生活质量。这些具体目标将 通过开发基因组编辑来解决庞培病早期治疗的需要，这将指导 未来临床试验的设计，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.