Biomarker signatures for duchenne muscular dystrophy - duchenne muscular dystrophy (DMD) is a debilitating muscle disease that remains without an effective treatment despite the accumulated…

Biomarker signatures for duchenne muscular dystrophy - duchenne muscular dystrophy (DMD) is a debilitating muscle disease that remains without an effective treatment despite the accumulated knowledge about the causative gene and muscle pathogenesis. Several clinical trials have failed partly because of a lack of reliable and sensitive outcome measures to assess disease progression and changes in disease course in response to an intervention. Current outcome measures such as timed physical tests and forced vital capacity (FVC) are laborious and often less objective than ideal, and moreover not sufficiently sensitive to detect meaningful short-term changes. We hypothesize that blood accessible biomarkers provide useful tools as surrogate outcome measures to monitor disease course and early changes in disease direction in DMD. Highly specific, precise, and reproducible analytical assays are needed to identify such biomarkers. We have extensively published on biomarker discoveries in DMD using somascan aptamer-based assay and mass spectrometry. The next step is to further develop and test biomarkers for their clinical utility. The goal of this R61/R33 proposal is to use a rigorous workflow to evaluate monitoring biomarker signatures that could be translated from bench to clinic and bench to clinical trials to help with drug development programs. We have generated strong preliminary data that support our hypothesis and feasibility. For the R61 phase, we propose two aims. Specific aim 1 is to develop reliable, specific, and accurate methods for discovery and measurement of serum protein biomarkers in DMD. Specific aim 2 is to define optimal monitoring biomarker signatures with robust statistical methods using longitudinal serum samples with clinical data collected from well-defined and well annotated cohorts. Specific aim 3 is to carry out an evaluation of the developed monitoring biomarker signatures in external independent samples (retrospective or prospective) using longitudinal sera samples and clinical data collected through independent cohorts. If successful, this proposal will provide proof of concept of monitoring biomarker signatures for DMD to help with go/no-go decision making in future short term clinical trials or in day to day clinical usage by a physician to judge disease burden and severity, i.e., sensitive to short-term changes in function and predictive of longer-term disease milestones.