Abstract
ABSTRACTClinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any clinical trial must be carefully pondered in order to minimize the risk of clinical trial withdrawal or failure. A rigorous distinction between proof-of-concept and preclinical efficacy studies using animal models is key to support the rationale of a clinical trial involving patients. This Review evaluates the experience accumulated by the TREAT-NMD Advisory Committee for Therapeutics, which provides detailed constructive feedback on clinical proposals for neuromuscular diseases submitted by researchers in both academia and industry, and emphasizes that a timely critical review of preclinical efficacy data from animal models, including biomarkers for specific diseases, combined with adherence to existing guidelines and standard protocols, can significantly help to de-risk clinical programs and prevent disappointments and costly engagement.
Highlights
Animal models of human genetic diseases are useful for several reasons
Launched in 2007, the EU-funded network of excellence for genetic neuromuscular diseases, Translational Research in Europe for the Assessment and Treatment of Neuromuscular Disorders (TREATNMD; FP6 contract number EC 036825), aimed at addressing the clinical translation problem by harmonizing best practices and tools in Europe to accelerate the development of effective treatments for neuromuscular diseases, with an initial focus on Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA)
In the preclinical research space, it was clear that the fragmentation of research approaches and the lack of guidelines to define the level of rigor required to promote a preclinical study for translation into humans were key aspects to address
Summary
Animal models of human genetic diseases are useful for several reasons They allow the study of mechanisms of a specific disease at different stages and in association with development, growth and aging, by sampling different types of tissues and fluids, and by assessing the animals functionally in a manner that is relevant to the disease. The network progressively developed additional guidelines and recommendations, and held workshops to improve the quality and robustness of preclinical studies, to increase transparency in reporting and as independent validation (Willmann et al, 2015, 2012) This effort with multiple stakeholders is highly dynamic, continuously involving novel animal models and technical advancement in experimental strategies (see for example Gordish-Dressman et al, 2018; Willmann et al, 2018)
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