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 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). Methods: BforSMA 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. Results: 12 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. Conclusions: Discovery 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.
Bibliographical noteFunding Information:
MGW and JS are employees/owners of Walker Biosciences statistical consulting group. LS, KB, RD and JM are employees of Myriad RBM, a for-profit company involved in producing research diagnostics. Myriad RBM sells the SMA-MAP panel. RL is a former employee of NERI, a for-profit clinical research organization. TP is the former employee of BG Medicine, a for-profit company involved in producing research diagnostics. RSF receives commercial research support from PTC Therapeutics, Santhera Pharmaceuticals, and Genzyme Corp., accepted travel stipends as part of grants from PTC Therapeutics, reviewed and prepared a report for Adibi legal proceeding, spends 50% of his professional time carrying out clinical studies, and serves on the medical advisory board of DuchenneConnect and Families of SMA and on the scientific advisory board of PTC Therapeutics. TOC serves on the medical and scientific advisory boards of Families of SMA, the medical board of the Muscular Dystrophy Association, and has served as frequent ad hoc advisor to the Scientific Advisory Board of the SMA Foundation. KJS serves on the scientific advisory boards of Families of SMA, the Pediatric Neurotransmitter Disorders Foundation, California Stem Cell, Inc., and the Alternating Hemiplegia of Childhood Foundation (AHCF). She serves as an ad-hoc reviewer for the Muscular Dystrophy Association (MDA) and National Institutes of Health (NIH). She has accepted research funds for consultation for Biomarin Pharmaceuticals and Shire, Inc. The SMA Foundation has filed a patent application on aspects of this work, International Patent Application No. PCT/US2010/048675, and Ref: SMAF- 005/01WO 304991-2019. A member of RSF’s immediate family receives commercial research support from Merck Pharmaceuticals, has received license fee payments from Southern Biotechnology Associates, Upstate Pharmaceuticals, and Santa Cruz Biotechnology, holds 6 patents or pending patents, contributes to other clinical research as a local co-investigator or PI in studies funded by the NIH and the UK, is the editor of Janeway Textbook of Immunology and Arthritis Research and Therapy, and devotes 33% of her professional time to clinical studies in her practice. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.