Longitudinal Assessment of Molecular and Imaging Biomarkers in LGMDR1

Summary/Abstract The limb girdle muscular dystrophies (LGMD) are a group of over 30 genetic muscle diseases which share a pattern of weakness affecting proximal muscles of the shoulders and hips. LGMD type R1 (LGMDR1) is the most common LGMD and is caused by mutation of the calpain 3 gene. There is no FDA approved treatment for LGMDR1, and patients experience progressive weakness and muscle wasting which can lead to loss of the ability to walk or maintain a job. Excitingly, recent advances in other muscle diseases give hope that LGMDR1 patients can be treated with gene therapies that replace the calpain 3 gene to restore its function to muscle. Five research groups already have calpain 3 gene replacement therapies in pre-clinical development. Additionally, non-specific therapies targeting muscle mass or function are in development for related diseases which may also prove beneficial for LGMDR1. Unfortunately, despite this excitement, the pace of therapeutic development has outpaced our ability to prepare for and evaluate efficacy in clinical trials. Towards this, there is a great need to develop muscle-based molecular and imaging biomarkers that can facilitate LGMDR1 clinical trials. Our goal in this Ancillary Project is to leverage the large LGMD natural history study of our Parent Project into reasonably validated molecular and imaging biomarkers with prognostic, predictive and pharmacodynamic value for LGMDR1. To accomplish this, we urgently need to add muscle biopsy, serum discovery assays, and MRI-based imaging protocols into that study. Doing so will allow us to benchmark molecular and imaging-based readouts against Clinical Outcome Assessments as well as Patient Reported Outcomes taken at the same time. Specifically, we plan to 1) assay properties of calpain 3 in muscle, 2) discover proteins and miRNAs that are disrupted by disease, and 3) assay quantitative MRI biomarkers in relation to upper limb function as well as muscle inflammation. All patients are followed longitudinally over a period of one year in order to correlate change in serum and MR biomarkers to change in clinical outcomes, with a focus on the North Star Assessment for LGMD as a functional measure. We are uniquely positioned to accomplish this project through our parent project “TREATing LGMDR1” and our LGMD Research Network (GRASP-LGMD), which is made up of 12 sites with standardized evaluator training. We hypothesize that calpain 3, molecular pathways, and MRI-based measurements will provide sensitive monitoring biomarkers that reflect disease progression and response to treatment. Our rationale is that by benchmarking biomarkers against clinical outcome assessments we can identify reasonably likely surrogate endpoints to facilitate therapeutic development.