227 th ENMC International Workshop:

Abstract

Grounds d on behalf of the 227th ENMC workshop study group 1

Multiomic characterization of disease progression in mice lacking dystrophin

“…A large number of therapeutic compounds ranging from small molecules to gene therapy have been tested in animal, especially in the mdx mouse. Despite efforts to harmonize the experimental procedures to assess muscle performance with physiologic and functional tests, the variation in mice performance, differences in study design across laboratories and lack of large confirmatory studies has resulted in a number drugs tested in exploratory preclinical studies being tested in clinical settings [53,54]. The inclusion of objective biomarkers to assess drug efficacy in pre-clinical settings has been proposed as a mechanism to improve the overall success of clinical trials where many failures have been observed [53].…”

“…Despite efforts to harmonize the experimental procedures to assess muscle performance with physiologic and functional tests, the variation in mice performance, differences in study design across laboratories and lack of large confirmatory studies has resulted in a number drugs tested in exploratory preclinical studies being tested in clinical settings [53,54]. The inclusion of objective biomarkers to assess drug efficacy in pre-clinical settings has been proposed as a mechanism to improve the overall success of clinical trials where many failures have been observed [53]. Failures may be the result of under-powered clinical trials or "noisy" outcome measures, however stringent evaluation of drugs at the preclinical stage with objective readouts could contribute to a better selection of medicinal products to be brought forward for clinical development.…”

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

“…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(Willmann et al, , 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).…”

“…TREAT-NMD also strived to consolidate a 'modus operandi' that could be widely accepted by the community for the sake of the community itself: all interested stakeholders, including editors and funding agencies, should be aware that the quality of preclinical data for translational research needs to be predominantly robust, reproducible and less focused on novel and sensational results (Willmann et al, 2018). This process can be in part ensured with a clear distinction between proof-of-concept preclinical studies, often aimed at target validation with an interesting candidate molecule, and clinically-oriented ones that are aimed at the translational effort and that are built with the rigor that resembles clinical trials and/or the toxicology data package required for drug approval (Grounds et al, 2008;Willmann et al, 2015).…”