McGraw Christopher M, Ward Christopher S, Samaco Rodney C
Department of Neurology, University of California, San Francisco, San Francisco, California.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas.
Am J Med Genet C Semin Med Genet. 2017 Sep;175(3):368-379. doi: 10.1002/ajmg.c.31570.
Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non-neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches.
神经行为障碍包括神经退行性疾病、神经发育障碍和精神疾病,它们共同构成了发病和死亡的主要原因。尽管学术界进行了大量研究,制药行业也付出了诸多努力,以阐明这些疾病中起作用的发病机制并开发基于机制的疗法,但我们的理解仍不完整,且难以获得有效的治疗干预措施。这些不足的程度可以通过越来越多令人失望的临床试验来衡量,这些试验基于在基因动物模型中最初显示出前景的化合物。本综述及评论将探讨为何会出现这种情况,重点关注神经行为障碍的基因模型在当前识别发病机制和疗法的努力中所占据的核心作用。特别是,我们将强调与非神经疾病的基因模型以及20世纪早期基于症状的模型相比,这些模型中阻碍成功的独特陷阱和挑战,正是那些早期模型促成了如今仍在使用的所有主要类别的精神活性药物化合物的发现。通过人类神经行为障碍的特定基因啮齿动物模型的实例,我们将突出可重复性、构建效度和转化相关性等问题,希望这些实例能为未来的研究取得更大成功提供指导。最后,我们将倡导一种双管齐下的方法来识别神经行为障碍的新疗法,除了更多基于机制的方法外,还要更多地利用历史上更成功的基于症状的方法。