Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models.
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.
['Hua|Yimin|Y|', 'Liu|Ying Hsiu|YH|', 'Sahashi|Kentaro|K|', 'Rigo|Frank|F|', 'Bennett|C Frank|CF|', 'Krainer|Adrian R|AR|']
D000818:Animals D002490:Central Nervous System D004195:Disease Models, Animal D015316:Genetic Therapy D051379:Mice D008822:Mice, Transgenic D009046:Motor Neurons D009134:Muscular Atrophy, Spinal D016376:Oligonucleotides, Antisense D010641:Phenotype D055532:SMN Complex Proteins
spinal muscular atrophy mouse models SMN antisense oligonucleotide SMN2