title: The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA), a leading genetic cause of pediatric death in the world, is an early-onset disease affecting the motor neurons in the anterior horn of the spinal cord. This degeneration of motor neurons leads to loss of muscle function. At the molecular level, SMA results from the loss of or mutation in the survival motor neuron 1 (SMN1) gene. The number of copies of the nearly duplicated gene SMN2 modulates the disease severity in humans as well as in transgenic mouse models for SMA. Most preclinical therapeutic trials focus on identifying ways to increase SMN2 expression and to alter its splicing. Other therapeutic strategies have investigated compounds which protect affected motor neurons and their target muscles in an SMN-independent manner. In the present study, the effect of a combination regimen of the SMN2 inducer D156844 and the protectant follistatin on the disease progression and survival was measured in the SMNΔ7 SMA mouse model. The D156844/follistatin combination treatment improved the survival of, delayed the end stage of disease in and ameliorated the growth rate of SMNΔ7 SMA mice better than follistatin treatment alone. The D156844/follistatin combination treatment, however, did not provide additional benefit over D156844 alone with respect to survival and disease end stage even though it provided some additional therapeutic benefit over D156844 alone with respect to motor phenotype.
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors.forename: Ashlee W
authors.initials: AW
authors.lastname: Harris
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA; Center for Pediatric Research, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA; Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, USA. Electronic address: butchbach@nemoursresearch.org.
authors.forename: Matthew E R
authors.initials: ME
authors.lastname: Butchbach
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D005260:Female; D038681:Follistatin / Q000008:administration & dosage* / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D011799:Quinazolines / Q000008:administration & dosage* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D038681:Follistatin; D011799:Quinazolines; D011994:Recombinant Proteins; C526473:Smn1 protein, rat; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D004722:Endoribonucleases; C508554:DcpS protein, mouse
keywords: 2,4-Diaminoquinazoline; D156844; Follistatin; Motor neuron disease; Neonatal mouse; Preclinical drug trial; Spinal muscular atrophy