title: Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration.
abstract: OBJECTIVE
  Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers.
  
  
  METHODS
  SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90.
  
  
  RESULTS
  Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO.
  
  
  CONCLUSIONS
  This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers.
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.|Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.
authors.forename: W David
authors.initials: WD
authors.lastname: Arnold
authors.affiliation: VIB Center for the Biology of Disease - KU Leuven Department of Human Genetics, Leuven Belgium, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duque
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.
authors.forename: Chitra C
authors.initials: CC
authors.lastname: Iyer
authors.affiliation: PharmOptima, Portage, Michigan, United States of America.
authors.forename: Phillip
authors.initials: P
authors.lastname: Zaworski
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: McGovern
authors.affiliation: PharmOptima, Portage, Michigan, United States of America.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: SMA Foundation, New York, New York, United States of America.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: von Herrmann
authors.affiliation: SMA Foundation, New York, New York, United States of America.
authors.forename: Dione T
authors.initials: DT
authors.lastname: Kobayashi
authors.affiliation: SMA Foundation, New York, New York, United States of America.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Chen
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.|Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kolb
authors.affiliation: SMA Foundation, New York, New York, United States of America.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Paushkin
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.|Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus Ohio, United States of America.
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006801:Humans; D007276:Injections, Intraventricular; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016376:Oligonucleotides, Antisense; C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein