Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

被引:53
作者
Bogdanik, Laurent P. [1 ]
Osborne, Melissa A. [1 ]
Davis, Crystal [1 ]
Martin, Whitney P. [1 ]
Austin, Andrew [1 ]
Rigo, Frank [2 ]
Bennett, C. Frank [2 ]
Lutz, Cathleen M. [1 ]
机构
[1] Jackson Lab, Genet Resource Sci, Bar Harbor, ME 04609 USA
[2] ISIS Pharmaceut, Carlsbad, CA 92010 USA
关键词
SMA; antisense oligonucleotide; neuromuscular junction; motor unit number estimation; NEUROMUSCULAR-JUNCTION; SMN EXPRESSION; NUMBER ESTIMATION; CARDIAC DEFECTS; NEURON GENE; SURVIVAL; MICE; PHENOTYPE; RESTORATION; PATHOLOGY;
D O I
10.1073/pnas.1509758112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.
引用
收藏
页码:E5863 / E5872
页数:10
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