Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy

Riddell, Dominique O; Hildyard, John C W; Harron, Rachel C M; Wells, Dominic J; Piercy, Richard J

Abstract

Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease affecting approximately 1 in 6000 male births worldwide. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying within the hotspot for human patients, making it especially valuable. Prior to conducting therapeutic trials using this novel animal model, it is essential to establish a panel of viable biomarkers.

Methods: We evaluated a panel of blood-borne biomarkers of musculoskeletal disease in the DE50-MD dog. Venous blood samples were obtained monthly throughout an 18-month study period in DE50-MD (N=18) and wild-type (WT) control (N=14) dogs. A panel of potential plasma/serum biomarkers of DMD was measured and their theoretical utility in future clinical trials determined using sample size calculations.

Results: Compared to WT dogs, DE50-MD dogs had substantially higher circulating creatine kinase (CK) activities, myomesin-3 (MYOM3), and the dystromiRs miR-1, miR-133a and miR-206, but significantly lower serum myostatin concentrations. An age-associated pattern, similar to that observed in DMD patients, was seen for CK and MYOM3. Sample size calculations suggested that low cohort sizes (N3) could be used to detect up to a 50% improvement from the DE50-MD and WT levels in each biomarker or a combination thereof (via principal component analysis); as few as N=3 animals should enable detection of a 25% improvement using a combined biomarker approach (alpha 0.05, power 0.8).

Conclusions: We have established a panel of biomarkers that could be used to monitor musculoskeletal disease or response to a therapeutic intervention in the DE50-MD dog using low numbers of animals. The blood biomarker profile closely mimics that of DMD patients, supporting the hypothesis that this DMD model would be suitable for use in pre-clinical trials.

Citation

Riddell, D. O., Hildyard, J. C. W., Harron, R. C. M., Wells, D. J., & Piercy, R. J. (in press). Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy. Wellcome Open Research, https://doi.org/10.12688/wellcomeopenres.17398.1

• Journal Article Type: Article
• Acceptance Date: Nov 10, 2021
• Online Publication Date: Jan 17, 2022
• Deposit Date: Nov 5, 2021
• Publicly Available Date: Feb 10, 2022
• Publisher: F1000Research
• Peer Reviewed: Not Peer Reviewed
• DOI: https://doi.org/10.12688/wellcomeopenres.17398.1
• Public URL: https://rvc-repository.worktribe.com/output/1552139