Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Mol Genet Metab. 2024 Sep-Oct;143(1-2):108559. doi: 10.1016/j.ymgme.2024.108559. Epub 2024 Aug 3.
Years of research into the structure, processing, and function of acid alpha-glucosidase led to the development and 2006 approval of alglucosidase alfa (recombinant human acid alpha-glucosidase, Myozyme®/Lumizyme®), an enzyme replacement therapy and the first approved treatment for Pompe disease. Alglucosidase alfa has been a lifesaving treatment for patients with infantile-onset Pompe disease and radically improved daily life for patients with late-onset Pompe disease; however, long-term experience with alglucosidase alfa unraveled key unmet needs in these populations. Despite treatment, Pompe disease continues to progress, especially from a skeletal muscle perspective, resulting in a multitude of functional limitations. Strong collaboration between the scientific and patient communities led to increased awareness of Pompe disease, a better understanding of disease pathophysiology, knowledge of the clinical course of the disease as patients surpassed the first decade of life, and the strengths and limitations of enzyme replacement therapy. Taken together, these advancements spurred the need for development of a next generation of enzyme replacement therapy and provided a framework for progress toward other novel treatments. This review provides an overview of the development of avalglucosidase alfa as a model to highlight the interaction between clinical experience with existing treatments, the role of the clinician scientist, translational research at both system and cellular levels, and the iterative and collaborative process that optimizes the development of therapeutics.
多年来对酸性α-葡萄糖苷酶的结构、加工和功能的研究，促成了阿加糖酶α（重组人酸性α-葡萄糖苷酶，Myozyme®/Lumizyme®）的开发和 2006 年的批准，这是一种酶替代疗法，也是首个获批用于庞贝病的治疗方法。阿加糖酶α挽救了婴儿型庞贝病患者的生命，并极大地改善了晚发型庞贝病患者的日常生活；然而，阿加糖酶α的长期应用揭示了这两个患者群体中的关键未满足需求。尽管进行了治疗，但庞贝病仍在进展，尤其是从骨骼肌的角度来看，导致多种功能受限。科学界和患者群体之间的紧密合作，提高了人们对庞贝病的认识，加深了对疾病病理生理学的理解，了解了患者超过生命最初十年后的疾病临床过程，以及酶替代疗法的优势和局限性。总之，这些进展促使人们需要开发下一代酶替代疗法，并为其他新型治疗方法的进展提供了框架。本文回顾了阿加糖酶α的开发历程，旨在突出现有治疗方法的临床经验、临床科学家的作用、系统和细胞水平的转化研究，以及优化治疗药物开发的迭代和协作过程之间的相互作用。
