期刊
GENES & DEVELOPMENT
卷 29, 期 3, 页码 288-297出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.256644.114
关键词
spinal muscular atrophy; SMN2; SMN; antisense oligonucleotide; mouse models
资金
- National Institutes of Health [R37 GM42699]
- St. Giles Foundation
- Cold Spring Harbor Laboratory (CSHL)
- Cancer Center Support Grant [5P30CA045508]
- National Natural Science Foundation of China [81271423, 81471298]
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.
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