PracticeUpdate: Neurology - Winter 2018

ICNMD 2018 23

Protein Biomarkers of Dysferlinopathy Identified Biomarkers show promise for evaluating and monitoring disease progression and predicting therapeutic effect

P rotein biomarkers of dysferlinopathy have been identified that hold promise for evalua- tion and monitoring, as well as for predicting therapeutic outcome, suggests a biomarker dis- covery program described at ICNMD 2018. Using multiple reaction monitoring, the best per- forming protein biomarker panel exhibited an area under receiver operating characteristics curve per- formance of 0.92 with 92% sensitivity and 76% specificity in study participants versus healthy controls. When this panel was tested in the external Clinical Outcome Study for Dysferlinopathy (COS; a multi- center, international, consortium study of the natural history of the disease coordinated by Volker Straub, MD, of the University of Newcastle, UK) replication cohort, area under the curve was 0.89. The best performing panel exhibited an area under the curve of 0.91 with 92% sensitivity and 79% specificity in ambulatory versus non-ambulatory participants. External replication performance of this multi- ple reaction monitoring panel in COS participants yielded an area under the curve of 0.77. Laura Rufibach, PhD, of the Jain Foundation in Seattle, Washington, explained that dysferlinopa- thy is a rare neuromuscular disease caused by a deficiency of the dysferlin protein. This deficiency results in progressive skeletal muscle weakness of the limbs, which often leads to an inability to walk.

The most common clinical presentations of dysfer- linopathy are limb-girdle muscular dystrophy type 2B and Miyoshi myopathy type 1. Due to the rare nature of the disease, molecular signatures that differentiate sufferers from healthy individuals, as well as levels of severity, have not been defined. Dr. Rufibach told Elsevier’s PracticeUpdate , “We have identified clinical outcome measures for future clinical trials in dysferlinopathy. For example, change is being captured in this population con- sistently over 1 year across a range of functional outcomes including the North Star Assessment for Dysferlinopathy, 10 meter walk, Timed Up and Go, and four stair climb and descend.” “Results of both the protein biomarker and COS studies will help us design and run effective clinical trials in dysferlinopathy. We expect to determine how biomarker panels change in patients treated with a potential therapeutic intervention such as gene therapy. The ultimate goal is to provide an effective treatment to those suffering from this debilitating disease,” Dr. Rufibach noted. In the pilot phase, participants were split into highly ambulant (n=25) and non-ambulant (n=25) groups to assess profiles associated with disease pro- gression and to compare profiles with those of healthy age- and sex- matched controls (n=25). Protein biomarkers were combined to improve on the performance of individual proteins. In the technical replication phase, the best-per- forming protein panels were recalibrated in the same individuals using a targeted platform (multi- ple reaction monitoring mass spectrometry). In the external replication phase, the multiple reac- tion monitoring panels with the best performance were analyzed in 145 baseline visit samples from the COS. In the longitudinal phase of the biomarker study, data from multiple reaction monitoring and clinical metrics from three time points from the COS (base- line and years 1 and 2) are being evaluated in 120 samples per visit to determine whether longitudinal protein data from multiple reaction monitoring can be used to stratify participants with dysferlinopathy with respect to future clinical outcome. “The main goals of COS are to better understand the natural progression of dysferlinopathy and to identify the best outcome measures to use in eval- uating potential therapies in clinical trials,” noted Dr. Rufibach. “We want to be ready to design and run effective clinical trials once these agents are identified. We are well on our way toward achiev- ing these goals. In addition to the promising protein biomarkers, the clinical analysis is showing slow but consistent, significant change over a years’ time in numerous functional and strength measures.” www.practiceupdate.com/c/70708

Dr. Laura Rufibach

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VOL. 3 • NO. 3 • 2018