Carias K Vanessa, Wevrick Rachel
Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
Mol Ther Methods Clin Dev. 2019 Mar 14;13:344-358. doi: 10.1016/j.omtm.2019.03.001. eCollection 2019 Jun 14.
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes, complicating the development of targeted therapeutics. Clinical trials are now underway in PWS, with more trials to be implemented in the next few years. PWS-like endophenotypes are recapitulated in gene-targeted mice in which the function of one or more PWS genes is disrupted. These animal models can guide priorities for clinical trials or provide information about efficacy of a compound within the context of the specific disease. We now review the current status of preclinical studies that measure the effect of therapeutics on PWS-like endophenotypes. Seven categories of therapeutics (oxytocin and related compounds, K-ATP channel agonists, melanocortin 4 receptor agonists, incretin mimetics and/or GLP-1 receptor agonists, cannabinoids, ghrelin agents, and [cactus] extract) have been tested for their effect on endophenotypes in both PWS animal models and clinical trials. Many other therapeutics have been tested in clinical trials, but not preclinical models of PWS or vice versa. Fostering dialogs among investigators performing preclinical validation of animal models and those implementing clinical studies will accelerate the discovery and translation of therapies into clinical practice in PWS.
普拉德-威利综合征（PWS）是一种罕见的神经发育障碍，可导致内分泌、肌肉骨骼和神经功能障碍。PWS是由相邻基因的失活引起的，这使得靶向治疗的开发变得复杂。目前正在进行针对PWS的临床试验，未来几年还将开展更多试验。在基因靶向小鼠中重现了类似PWS的内表型，其中一个或多个PWS基因的功能被破坏。这些动物模型可以指导临床试验的重点，或在特定疾病背景下提供有关化合物疗效的信息。我们现在回顾临床前研究的现状，这些研究测量了治疗方法对类似PWS内表型的影响。七类治疗方法（催产素及相关化合物、钾离子通道激动剂、黑皮质素4受体激动剂、肠促胰岛素类似物和/或胰高血糖素样肽-1受体激动剂、大麻素、胃饥饿素制剂和[仙人掌]提取物）已在PWS动物模型和临床试验中测试了它们对内表型的影响。许多其他治疗方法已在临床试验中进行了测试，但未在PWS临床前模型中进行测试，反之亦然。促进在对动物模型进行临床前验证的研究人员与开展临床研究的人员之间的对话，将加速PWS治疗方法的发现并将其转化为临床实践。
