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PMID: 25583329 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models.

Genes & development ·Vol. 29 ·No. 3 ·2015-02-01 ·Pages 288-97

Hua Y, Liu YH, Sahashi K, Rigo F, Bennett CF, Krainer AR

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.

Keywords
SMN SMN2 antisense oligonucleotide mouse models spinal muscular atrophy
MeSH Terms
Animals Central Nervous System/cytology,metabolism Disease Models, Animal Genetic Therapy Mice Mice, Transgenic Motor Neurons/cytology,metabolism Muscular Atrophy, Spinal/genetics,physiopathology,therapy Oligonucleotides, Antisense/genetics,metabolism,therapeutic use Phenotype SMN Complex Proteins/genetics,metabolism
Chemicals
Oligonucleotides, Antisense SMN Complex Proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hua Yimin
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; [email protected] [email protected] [email protected].
Liu Ying Hsiu
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
Sahashi Kentaro
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
Rigo Frank
Isis Pharmaceuticals, Carlsbad, California 92010, USA.
Bennett C Frank
Isis Pharmaceuticals, Carlsbad, California 92010, USA.
Krainer Adrian R
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; [email protected] [email protected] [email protected].
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.256644.114
Email
[email protected]
[email protected]
[email protected]
Published
2015-02-01
Epub
2015-00-12
Pages
288-97
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC4318145
Subset
IM
Grants
NCI NIH HHS · P30 CA045508 · United States
NIGMS NIH HHS · R37 GM042699 · United States
NCI NIH HHS · 5P30CA045508 · United States
NIGMS NIH HHS · R37 GM42699 · United States
External Links
PubMed source DOI: 10.1101/gad.256644.114 PMC Full Text View journal details
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