@article{0d114040ef4b49c5a18083007ca6ea08,
title = "Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study",
abstract = "Background: The universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early {"}biomarker{"} of treatment effect. Methods: A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age. Results: SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other. Conclusion: This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an {"}early look{"} for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number. Trial Registry: Clinicaltrials.gov NCT00756821.",
author = "{Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group} and Crawford, {Thomas O.} and Paushkin, {Sergey V.} and Kobayashi, {Dione T.} and Forrest, {Suzanne J.} and Joyce, {Cynthia L.} and Finkel, {Richard S.} and Petra Kaufmann and Swoboda, {Kathryn J.} and Danilo Tiziano and Rosa Lomastro and Li, {Rebecca H.} and Trachtenberg, {Felicia L.} and Thomas Plasterer and Chen, {Karen S.} and M. Bell and D. Jacoby and R. McBurney and W. Chung and L. Simard and M. Sahin",
note = "Funding Information: This study acknowledges the collaboration of the International Spinal Muscular Atrophy Patient Registry (Indiana University), supported by the Patient Advisory Group of the International Coordinating Committee for SMA Clinical Trials which includes Families of SMA, FightSMA, Muscular Dystrophy Association, SMA Foundation, and other SMA advocacy groups. Funding Information: Dr. Crawford 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. He has received research support for clinical studies from Families of SMA, SMA Foundation, and the Ataxia Telangiectasia Children{\textquoteright}s Project.; Dr. Paushkin is an employee of the SMA Foundation.; Dr. Kobayashi is an employee of the SMA Foundation.; Ms. Forrest was an employee of the SMA Foundation during the time of the study.; Ms. Joyce was an employee of the SMA Foundation during the time of the study.; Dr. Finkel receives commercial research support from PTC Therapeutics, Santhera Pharmaceuticals, and Genzyme Corp. and non-profit research support from the SMA Foundation and support from the NIH/NIAMS and NIH/NINDS, accepted travel stipends as part of grants from PTC Therapeutics and the SMA Foundation, 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. A member of his immediate family receives commercial research support from Merck Pharmaceuticals, has received license fee payments from Southern Biotechnology Associates, Upstate Pharmaceuticals, and Santa Cruz Biotechnology, receives research funding from the NIH (grant #s: AR058606, 1R21 AI078387, 1R21 AI078387-S1, 1R41 AI071927, R01 AI063623, 1U19AI082726, T32; pending grant #s: 1R21, AR059466, T32, AR059650), 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.; Dr. Kaufmann is an employee of the federal government and has no disclosures. Prior to August 2009, Dr. Kaufmann was an employee of Columbia University and received research support from the NIH, the SMA Foundation, PTC, Santhera Pennwest and the DoD. This report is based on Dr. Kaufmann{\textquoteright}s work at Columbia University and is not related to the National Institutes of Health.; Dr. Swoboda 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 NIH. She has accepted research funds for consultation for Biomarin Pharmaceuticals and Shire, Inc. She receives or has received in the past year grant funding from Families of SMA, MDA, FightSMA, AHCF and NIH (R01-HD054599; ARRA 5-R01 HD054599-04, and 1-R01-HD69045 from NICHD).; Dr. Tiziano reports no disclosures.; Dr. Lomastro reports no disclosures.; Dr. Li is employed by New England Research Institutes (NERI). NERI was paid by the sponsoring organization of this study to coordinate this study and perform additional analyses.; Dr. Trachtenberg is employed by New England Research Institutes (NERI). NERI was paid by the sponsoring organization of this study to coordinate this study and perform additional analyses.; Dr. Plasterer was employed by BG Medicine (BGM) from July 2001-March 2010. BGM was paid by the sponsoring organization of this study for sample and statistical analysis.; Dr. Chen is an employee of the SMA Foundation.; This does not alter our adherence to all the PLoS ONE policies on sharing data and materials. ",
year = "2012",
month = apr,
day = "27",
doi = "10.1371/journal.pone.0033572",
language = "English (US)",
volume = "7",
journal = "PloS one",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",
}