Researchers identify blood markers to track muscular dystrophy gene therapy

<p>Introduction: Identifying serum biomarkers that reflect the restoration of dystrophin in skeletal muscle is important for eval-uating the effect of dystrophin-restoring therapies in preclinical and clinical trials. Many potential blood biomarkers have beenidentified in Duchenne muscular dystrophy (DMD) patients, which change with disease progression or respond to pharmacologi-cal treatment. In this study, it was suggested that a panel of such blood biomarker candidates could be used to monitor dystrophinrescue in mdx mice treated with microdystrophin based therapies.Methods: Plasma samples from mdx mice treated with the microdystrophin therapy SGT- 001 were analysed with an antibodysuspension bead array consisting of 87 antibodies. The array targets 83 unique proteins previously identified as biomarker can-didates for DMD. Each sample was assayed at two different plasma dilutions to cover a broader concentration range. Proteinconcentrations estimated as Median fluorescent intensities (MFI) were correlated to dystrophin expression in muscle tissue, asmeasured by immunohistochemistry and Western blot. Thirteen of the targets were selected and analysed in a DMD and Beckermuscular dystrophy (BMD) longitudinal natural history cohort using a suspension bead array.Results: Ten proteins were found to be significantly elevated in untreated mdx mice compared with C57 wild- type mice andto correlate with dystrophin expression (Spearman's correlation, FDR &lt; 0.05) upon gene transfer in mdx mice. Translatability ofthese biomarkers from animal models to patients was evaluated by exploring abundance trajectories over time in both DMD andBMD patients and association with dystrophin expression in BMD patients. Consistent with the observations in mouse, six ofthese biomarker candidates were more abundant in DMD patients compared with controls, and six were also differentially abun-dant between BMD and DMD patients. Among them, serum titin was shown to be associated with dystrophin expression in BMDpatients, having a steeper decline over time in patients with low dystrophin expression in tibialis anterior compared with patientswith high expression. Myosine light chain 3 had a steeper decline with time in DMD patients compared with BMD patients.Conclusions: The 10 biomarker candidates identified in mouse plasma are related to muscle contraction, glycolysis, microtubuleformation and protein degradation. Human titin and myosine light chain 3 were the most interesting candidates as explorativebiomarkers to monitor microdystrophin expression in gene therapies. If confirmed, these biomarkers could be used to detect restoration of dystrophin expression per se, monitor changes in dystrophin expression over time and potentially confirm diseasephenotype changes from severe to mild disease forms.</p>