TY - JOUR
T1 - Candidate proteins, metabolites and transcripts in the biomarkers for spinal muscular atrophy (BforSMA) clinical study
AU - Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group
AU - Finkel, Richard S.
AU - Crawford, Thomas O.
AU - Swoboda, Kathryn J.
AU - Kaufmann, Petra
AU - Juhasz, Peter
AU - Li, Xiaohong
AU - Guo, Yu
AU - Li, Rebecca H.
AU - Trachtenberg, Felicia
AU - Forrest, Suzanne J.
AU - Kobayashi, Dione T.
AU - Chen, Karen S.
AU - Joyce, Cynthia L.
AU - Plasterer, Thomas
AU - Krosschell, K. J.
AU - Maczulski, J. A.
AU - Crawford, T. O.
AU - Scott, C.
AU - Bell, M.
AU - Donahoo, K.
AU - Jacoby, D.
AU - McBurney, R.
AU - Sahin, M.
N1 - 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. 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. 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’s Project. 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. 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’s work at Columbia University and is not related to the National Institutes of Health. Drs. Juhasz, X. Li, and Guo are employed by BG Medicine (BGM). BGM was paid by the sponsoring organization of this study for sample and statistical analysis. Drs. R Li and Trachtenberg are 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. Ms. Forrest and Ms. Joyce were employed of the SMA Foundation during the time of the study. Dr. Chen and Dr. Kobayashi are paid employees of the SMA Foundation. 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. 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 Dr. Finkel’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, 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. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
PY - 2012/4/27
Y1 - 2012/4/27
N2 - Background: Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets. Objective: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches. Materials and Methods: A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures. Results: A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS. Discussion: In this cross-sectional study, "BforSMA" (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design. Trial Registry: Clinicaltrials.gov NCT00756821.
AB - Background: Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets. Objective: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches. Materials and Methods: A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures. Results: A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS. Discussion: In this cross-sectional study, "BforSMA" (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design. Trial Registry: Clinicaltrials.gov NCT00756821.
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U2 - 10.1371/journal.pone.0035462
DO - 10.1371/journal.pone.0035462
M3 - Article
C2 - 22558154
AN - SCOPUS:84860476261
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 4
M1 - e35462
ER -