Background:
Optimizing preclinical tools and methods to evaluate therapeutic candidates is critical to improve decision-making about advancing therapies to clinical testing. In 2016, in collaboration with leading experts in the neuromuscular community, Charley’s Fund, a patient-founded research nonprofit, launched an effort to address a timely topic of this nature: how to utilize a promising newer mouse model, the D2.B10-Dmdmdx/J (D2/mdx), speculated to recapitulate human pathology better than the commonly used C57BL/10ScSn-Dmdmdx/J (Bl10/mdx).
Objective:
Identify and act on opportunities to improve DMD preclinical best practices through a collaborative, data-driven, multi-stakeholder approach.
Approach:
Working groups collected and analyzed D2/mdx and Bl10/mdx data from multiple academic and industry sources. Nearly 18,000 data points on mutant and WT strains were gathered spanning 10 labs worldwide. 22 organizations across academia, nonprofits, and industry convened to review and discuss. A workshop report highlighted initial findings and opportunities.
Results:
In addition to identifying best practices and data gaps in the two models, the cross-lab data comparison identified notable differences in practices and results, even in labs of leading experts. First, no single outcome was assessed across all 10 labs. Most commonly assessed was body weight in 6 labs, followed by serum creatine kinase in 5. Second, labs often used different protocols for the same measure, with assessments for muscle performance in particular yielding variable outcomes. Third, inconsistencies existed in control arm design and use of vehicle, sham, and untreated mice.
To address these opportunities for improved consistency, quality, and coordination in DMD preclinical research: 1) a workshop report published preliminary findings, and 2) a well-powered 52-wk natural history study informed by the workshop results has been designed and funded to run in parallel in two leading DMD labs.