Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem.
Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem.
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发表时间：
2016-06
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通讯作者：
S. Macauley
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作者：
S. Macauley
溶酶体贮积病（lsd）是一组40-50罕见的单基因疾病，导致溶酶体功能紊乱和随后的溶酶体病理。根据与每种疾病相关的蛋白质或酶缺乏，lsd会影响一系列器官系统，并引发一套复杂的继发性疾病机制，使许多这些疾病难以完全治疗。大多数lsd的病因是已知的，溶酶体酶的先天生物学倾向于治疗干预，但大多数用酶替代策略治疗lsd的尝试都无法治愈。即使有了更复杂的方法，如底物还原疗法、药物伴侣疗法、基因疗法或干细胞疗法，对lsd的综合治疗仍未实现。考虑到单独治疗的局限性，最近的研究集中在使用联合方法来治疗lsd。通过将基于蛋白质、细胞和基因的治疗方法与小分子药物结合起来，研究人员在根除疾病的临床特征方面取得了更大的成功。本综述旨在讨论用于治疗lsd的单一疗法的积极和消极作用，并讨论如何将研究结合起来，在病理和功能参数上显示出更全面的益处。通过优化给药途径、治疗时间和针对继发性疾病机制，联合治疗代表了LSD治疗的未来。
Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs affect an array of organ systems and elicit a complex set of secondary disease mechanisms that make many of these disorders difficult to fully treat. The etiology of most LSDs is known and the innate biology of lysosomal enzymes favors therapeutic intervention, yet most attempts at treating LSDs with enzyme replacement strategies fall short of being curative. Even with the advent of more sophisticated approaches, like substrate reduction therapy, pharmacologic chaperones, gene therapy or stem cell therapy, comprehensive treatments for LSDs have yet to be achieved. Given the limitations with individual therapies, recent research has focused on using a combination approach to treat LSDs. By coupling protein-, cell-, and gene- based therapies with small molecule drugs, researchers have found greater success in eradicating the clinical features of disease. This review seeks to discuss the positive and negatives of singular therapies used to treat LSDs, and discuss how, in combination, studies have demonstrated a more holistic benefit on pathological and functional parameters. By optimizing routes of delivery, therapeutic timing, and targeting secondary disease mechanisms, combination therapy represents the future for LSD treatment.