Identification of serum protein biomarkers for utrophin based DMD therapy

Simon Guiraud,Huijia Chen,Kay E Davies,Nandini Shah,Adam Berg,Benjamin Edwards,Sarah E Squire,Arran Babbs

doi:10.1038/srep43697

Abstract

Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic.

Highlights

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene[1]
We have focused on utrophin modulation because it is applicable to all DMD patients irrespective of their dystrophin mutation
The effective execution of clinical trials in DMD has been severely hampered by the lack of robust biomarkers

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene[1]. We have reported a second generation compound, chemically related to Ezutromid, with improved physicochemical properties and a robust metabolism profile which ameliorates sarcolemmal stability and prevents the pathology through a significant reduction of regeneration, necrosis and fibrosis and provides functional enhancement[21] These data emphasize the potential of utrophin modulation as a disease-modifying therapeutic strategy for all DMD patients. Most clinical trials for DMD rely on standardized physical assessments such as the 6 minute walk distance test (6MWDT)[41], the North Star Ambulatory Assessment (NSAA)[42] as well as quantitative muscle strength tests[43,44] These physical tests are useful readouts for determining the whether a treatment slows disease progression but these endpoints are limited to ambulatory patients only, often challenging to implement specially in young patients and suffer from high inter-patient variability due to the variable natural history of the disease

Methods

Results

Conclusion