title: Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models.
abstract: Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; krainer@cshl.edu huay@cshl.edu ymhua@suda.edu.cn.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Ying Hsiu
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sahashi
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; krainer@cshl.edu huay@cshl.edu ymhua@suda.edu.cn.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D010641:Phenotype; D055532:SMN Complex Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D055532:SMN Complex Proteins
keywords: SMN; SMN2; antisense oligonucleotide; mouse models; spinal muscular atrophy