University of Mainz, Children's Hospital, Langenbeckstrasse 1, Mainz, Germany.
Expert Opin Emerg Drugs. 2010 Sep;15(3):495-507. doi: 10.1517/14728214.2010.498580.
Because orphan drug regulations encouraged development of drugs for rare disorders by granting marketing exclusivity for many years and other commercial benefits, treatment has become achievable for a few lysosomal storage disorders also. The presently available therapies, however, are not able to address all aspects of these multisystemic disorders and do not cure the patient. Therefore, there is a need for producing new drugs that are based on known pathophysiological mechanisms, such as enzyme replacement or inhibition of substrate synthesis, or which use new approaches to prevent the build-up of storage material.
New compounds that are being designed by different pharmaceutical companies can be divided in two groups, enzyme targeted and substrate targeted drugs. Enzyme targeted drugs include substances that modify the enzyme to make it more accessible to organs such as the bone or the brain, enhance enzyme activity (chaperones) or activate enzyme synthesis by small molecules that induce read-through of premature stop codons of genes that bear a nonsense mutation. To the group of substrate targeted drugs belong substances that inhibit the synthesis or modify the structure of the substrate (substrate deprivation or substrate optimization, respectively). For this review, a literature research has been undertaken that covers the years 1968 - 2010.
The reader of this paper will get an overview of drugs for lysosomal storage disorders that are on the market or are under development. This will help in the understanding of the pathophysiological mechanisms that underlie these rare metabolic diseases. In addition, the reader should realize that the increasing number of these very expensive drugs may lead to significant consequences for the health economic system.
In the last years, the interest of scientists and pharmaceutical companies in lysosomal storage disorders has increased dramatically, leading to the production of a rising number of different drugs. These drugs act at several stages of the pathophysiological cascade, for example, at the level of the substrate (substrate deprivation) or of the enzyme (enzyme enhancement). The presently available treatments are not able to address all clinical manifestations of these disorders, and it will still take a long time until new drugs are developed that are capable of curing the patients.
由于孤儿药法规鼓励开发药物的罕见疾病，给予市场独占权多年和其他商业利益，治疗已成为可能的一些溶酶体贮积症也。目前现有的治疗方法，然而，不能够解决这些多系统疾病的所有方面，也不能治愈病人。因此，有必要生产新的药物，这是基于已知的病理生理机制，如酶替代或抑制底物的合成，或使用新的方法来防止储存材料的积累。
不同的制药公司正在设计的新化合物可以分为两组，酶靶向和底物靶向药物。酶靶向药物包括修饰酶，使其更容易进入器官如骨或脑的物质，提高酶活性（伴侣）或激活酶合成的小分子，诱导通读的提前终止密码子的基因，承担无意义的突变。对组的底物靶向药物属于抑制合成或修饰的结构的底物（底物剥夺或底物优化，分别）。为了这篇综述，进行了文献研究，涵盖了 1968 年至 2010 年。
读者将获得的概述为溶酶体贮积症的药物在市场上或正在开发中。这将有助于理解这些罕见的代谢性疾病的病理生理机制。此外，读者应该意识到，越来越多的这些非常昂贵的药物可能会导致对卫生经济系统的重大影响。
在过去的几年中，科学家和制药公司对溶酶体贮积症的兴趣大大增加，导致生产越来越多的不同的药物。这些药物在病理生理级联的几个阶段起作用，例如，在底物（底物剥夺）或酶（酶增强）的水平。目前现有的治疗方法不能够解决这些疾病的所有临床表现，还需要很长时间才能开发出新的药物，能够治愈病人。
