Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders pres...Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders presents enormous challenges. A large range of therapeutic approaches across a diverse collection of brain disorders have been found to show great promise in preclinical testing and then failed during clinical trials. There are a variety of potential reasons for such failures, on both the preclinical and clinical sides of the equation. In this article, I wi l l focus on the key issues of validity in animal models. I wi l l discuss two forms of construct validity,‘genetic construct validity’ and ‘environmental construct val idity’,which model specific aspects of the genome and ‘envirome’ relevant to the disorder in question. The generation of new gene-edited animal models has been facilitated by new technologies, the most notable of which are CRISPR-Cas systems. These and other technologies can be used to enhance contruct validity. Finally, I wi l l discuss how face validity can be optimized, via more sophisticated cognitive, affective and motor behavioural tests, translational tools and the integration of molecular, cellular and systems data. Predictive validity cannot yet be assessed for the many preclinical models where we currently lack effective clinical interventions, however this wi l l change as the translational pipeline is honed to deliver therapies for a range of devastating disorders.展开更多
文摘Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders presents enormous challenges. A large range of therapeutic approaches across a diverse collection of brain disorders have been found to show great promise in preclinical testing and then failed during clinical trials. There are a variety of potential reasons for such failures, on both the preclinical and clinical sides of the equation. In this article, I wi l l focus on the key issues of validity in animal models. I wi l l discuss two forms of construct validity,‘genetic construct validity’ and ‘environmental construct val idity’,which model specific aspects of the genome and ‘envirome’ relevant to the disorder in question. The generation of new gene-edited animal models has been facilitated by new technologies, the most notable of which are CRISPR-Cas systems. These and other technologies can be used to enhance contruct validity. Finally, I wi l l discuss how face validity can be optimized, via more sophisticated cognitive, affective and motor behavioural tests, translational tools and the integration of molecular, cellular and systems data. Predictive validity cannot yet be assessed for the many preclinical models where we currently lack effective clinical interventions, however this wi l l change as the translational pipeline is honed to deliver therapies for a range of devastating disorders.
