Sanofi, Cambridge, MA, USA.
Sanofi, Cambridge, MA, USA.
Mol Genet Metab. 2024 Nov;143(3):108590. doi: 10.1016/j.ymgme.2024.108590. Epub 2024 Oct 11.
Pompe disease is a debilitating and life-threatening disease caused by aberrant accumulation of glycogen resulting from reduced acid alpha-glucosidase activity. The first treatment for Pompe disease, the enzyme replacement therapy, Myozyme® (recombinant human acid alpha-glucosidase, alglucosidase alfa), is a lifesaving treatment for the most severe form of the disease and provided clinically meaningful benefits to patients with milder phenotypes. Nonetheless, many patients display suboptimal responses or clinical decline following years of alglucosidase alfa treatment. The approval of avalglucosidase alfa (Nexviazyme®) and cipaglucosidase alfa (Pombiliti®) with miglustat (Opfolda®) represents a new generation of enzyme replacement therapies seeking to further improve patient outcomes beyond alglucosidase alfa. However, the emergence of a complicated new phenotype with central nervous system involvement following long-term treatment, coupled with known and anticipated unmet needs of patients receiving enzyme replacement therapy, has prompted development of innovative new treatments. This review provides an overview of the challenges of existing treatments and a summary of emerging therapies currently in preclinical or clinical development for Pompe disease and related lysosomal storage disorders. Key treatments include tissue-targeted enzyme replacement therapy, which seeks to enhance enzyme concentration in target tissues such as the central nervous system; substrate reduction therapy, which reduces intracellular glycogen concentrations via novel mechanisms; and gene therapy, which may restore endogenous production of deficient acid alpha-glucosidase. Each of these proposed treatments shows promise as a future therapeutic option to improve quality of life in Pompe disease by more efficiently treating the underlying cause of disease progression: glycogen accumulation.
庞贝病是一种进行性和危及生命的疾病，由酸性α-葡萄糖苷酶活性降低导致糖原异常积累引起。庞贝病的第一种治疗方法，酶替代疗法，Myozyme®（重组人酸性α-葡萄糖苷酶，阿糖苷酶α），是该病最严重形式的救命治疗方法，并为症状较轻的患者提供了有临床意义的益处。尽管如此，许多患者在接受多年的阿糖苷酶α治疗后，表现出不理想的反应或临床恶化。阿伐糖苷酶α（Nexviazyme®）和西普葡萄糖苷酶α（Pombiliti®）与米格列醇（Opfolda®）的批准代表了新一代酶替代疗法，旨在超越阿糖苷酶α进一步改善患者的治疗效果。然而，在长期治疗后出现伴有中枢神经系统受累的复杂新型表型，加上接受酶替代疗法的患者已知和预期的未满足需求，促使开发了创新的新疗法。这篇综述概述了现有治疗方法的挑战，并总结了目前处于临床前或临床开发阶段的用于庞贝病和相关溶酶体贮积症的新兴疗法。主要治疗方法包括组织靶向酶替代疗法，旨在通过新型机制提高目标组织（如中枢神经系统）中的酶浓度；底物减少疗法，通过降低细胞内糖原浓度来减少细胞内糖原浓度；和基因疗法，可能恢复内源性缺乏酸性α-葡萄糖苷酶的产生。这些拟议的治疗方法都有望成为改善庞贝病生活质量的未来治疗选择，通过更有效地治疗疾病进展的根本原因：糖原积累。
