Ries Markus
Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Center for Rare Disorders, Heidelberg University Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
J Inherit Metab Dis. 2017 May;40(3):343-356. doi: 10.1007/s10545-017-0032-8. Epub 2017 Mar 17.
Lysosomal storage disorders are strong candidates for the development of specific innovative therapies. The discovery of enzyme deficiencies is an important milestone in understanding the underlying cause of disease. Being able to replace the first missing enzyme in a lysosomal storage required three decades of dedicated research. Successful drug development for lysosomal storage disorders was fostered by the U.S. Orphan Drug Act. Various optimization strategies have the potential to overcome the current limitations of enzyme replacement therapies. In addition, substrate reduction therapies are an alternative approach to treat lysosomal storage disorders, chemical chaperones enhance residual enzyme activity, and small molecules can facilitate substrate transport through subcellular compartments. Bone-marrow derived multipotent stem cells and gene therapies have received FDA orphan drug designation status. The science of small clinical trials played an essential role: non-neurological endpoints, biomarker, and regulatory alignment are key factors in successful drug development for lysosomal storage disorders. Being able to treat brain disease is the next frontier. This review is dedicated to the memory of Roscoe O. Brady, an early pioneer in the research of lysosomal storage diseases.
溶酶体贮积症是开发特定创新疗法的有力候选对象。酶缺陷的发现是理解疾病根本原因的一个重要里程碑。能够替代溶酶体贮积中首个缺失的酶需要三十年的专注研究。美国《孤儿药法案》推动了溶酶体贮积症的成功药物研发。各种优化策略有可能克服当前酶替代疗法的局限性。此外，底物减少疗法是治疗溶酶体贮积症的另一种方法，化学伴侣可增强残余酶活性，小分子可促进底物通过亚细胞区室的运输。骨髓来源的多能干细胞和基因疗法已获得美国食品药品监督管理局（FDA）的孤儿药认定地位。小型临床试验科学发挥了至关重要的作用：非神经学终点、生物标志物和监管一致性是溶酶体贮积症成功药物研发的关键因素。能够治疗脑部疾病是下一个前沿领域。本综述谨献给溶酶体贮积病研究的早期先驱罗斯科·O·布雷迪。
