SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Dione Kobayashi ,Michael G Walker,Thomas O Crawford,Darryl C De Vivo,Michael P Mcdermott,Rebecca Li,Jing Shi,Douglas M Sproule,Kathryn J Swoboda,Brett Chung,Kathleen Mccarthy,Laurie Stephen,Richard S Finkel,Basil T Darras,Karen S Chen,Ruth Dewey,Cynthia Joyce,Petra Kaufmann,Wendy K Chung,William Martens ,James P Mapes ,Thomas N Plasterer ,Karri Ballard

doi:10.1371/journal.pone.0060113

Abstract

ObjectivesSpinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).MethodsBforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.Results12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.ConclusionsDiscovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

Highlights

Spinal Muscular Atrophy (SMA) is a rare genetic neuromuscular disease caused by the loss of the Survival Motor Neuron 1 gene (SMN1)
Several motor function scales, quality of life scales
The discovery phase yielded 35 putative SMA biomarkers selected to progress into the validation phase

Summary

Introduction

Spinal Muscular Atrophy (SMA) is a rare genetic neuromuscular disease caused by the loss of the Survival Motor Neuron 1 gene (SMN1). SMA is the epitome of a disease with high unmet medical need, as 1) there is no effective treatment, 2) the most severely affected patients succumb to respiratory failure, and 3) all patients experience significant progressive functional decline and morbidity due to extreme muscle weakness and atrophy. Several motor function scales (including SMA-specific measures like the Hammersmith Motor Function Scale or HFMS), quality of life scales

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