“Of Mice and Measures”: A Project to Improve How We Advance Duchenne Muscular Dystrophy Therapies to the Clinic

Abstract

A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information and their potential value. The overall aim is to establish guidance on how to best use the D2/mdx mouse model in preclinical studies.

Mouse models for muscular dystrophies: an overview

“…For example, the dystropathology worsens when mdx mice are bred on the DBA2/J background. The muscle function of this strain, called D2-mdx, is severely affected; their muscles are atrophic with extensive fibrosis and initial calcification that largely disappears with age (Coley et al, 2016;Gordish-Dressman et al, 2018;van Putten et al, 2019). Lastly, there are also several immunedeficient mdx strains, and mdx strains with mutations in additional genes as described in McGreevy et al (2015).…”

“…This call arose due to the failure of several drugs in clinical trials despite encouraging preclinical data (Kornegay et al, 2014;Straub and Mercuri, 2018). As such, multiple international initiatives aim to improve preclinical trial design and execution (Gordish-Dressman et al, 2018;Heslop et al, 2015;Nagaraju et al, 2009). The TREAT-NMD Alliance has coordinated the generation and maintenance of standard operating procedures (SOPs) for several widely used outcome measures for the most commonly used mouse models of Duchenne muscular dystrophy (DMD) (Nagaraju et al, 2009;Willmann et al, 2011a), spinal muscular atrophy (SMA) (Willmann et al, 2011b) and CMD (Saunier et al, 2016).…”

The use of genetically humanized animal models for personalized medicine approaches

“…Similarly, Young et al used Cas9 and guide RNAs targeting introns 44 and 45 to delete exon 45 in the hDMD gene, thus generating the hDMDdel45/mdx model (Young et al, 2017). The latter was backcrossed to the DBA/2J background, which is known to develop more severe fibrosis at early stages of the DMD disease (Gordish-Dressman et al, 2018;Heydemann et al, 2005;Coley et al, 2016;van Putten et al, 2019).…”

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).…”