SMA-MAP: a plasma protein panel for spinal muscular atrophy.

Objectives Spinal 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 SMAmotor 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 SMApatients collected from a multi-site natural history study(NHS). Methods BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMAmotor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMAtype 1, 2, and 3 samples (N = 158) from an SMANHS. 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 modelto predict SMAmotor function scores. Results 12 of the 35 putative SMAbiomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMAoutcome 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. Conclusions Discovery and validation using independent cohorts yielded a set of SMAbiomarkers significantly associated with motor function and other measures of SMAdisease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMAcollections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMAtherapies, and for predicting functional changes over time in SMApatients.