期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 22, 页码 6265-6277出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv329
关键词
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资金
- Wellcome Trust [097815/Z/11/Z]
- UCL Biomedical Research Centre [CBRC 161]
- Medical Research Council [MR/L013142/1]
- UCL SLMS Capital Equipment Funding
- Wellcome Trust/DOH fund
- Great Ormond Street Hospital Children's Charity
- Great Ormond Street Hospital Biomedical Research Centre
- UCL Biomedical Research Centre
- MRC
- AFM
- Wellcome Trust [097815/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MR/L013142/1, MR/K000608/1] Funding Source: UKRI
- Medical Research Council [MR/L013142/1, MR/K000608/1] Funding Source: researchfish
The human SMN2 transgenic mice arewell-established models of spinal muscular atrophy (SMA). While the severe type I mouse model has a rapidly progressive condition mimicking type I SMA in humans, the mild type III mice do not faithfully recapitulate chronic SMA variants affecting children. A SMA mouse model that clinically mimics the features of type II and III SMA in human is therefore needed. In this study, we generated intermediately affected SMA mice by delivering low-dose morpholino oligomer (PMO25) into the existing severe SMA mice. We show that a single low-dose administration of PMO25 moderately extended the survival of severe type I SMA mice. The neuromuscular pathology is also modestly but significantly improved in these mice. A second administration of PMO25 at postnatal day 5 (PND5) demonstrated an additive effect on survival. Additional systemic administration of low-dose PMO25 at 2-week intervals suppressed the occurrence of distal necrosis beyond postnatal day 100, and induced more complete phenotypic rescue than a single bolus high-dose injection at PND0. Our study demonstrates that survival of motor neuron (SMN) is required early at a critical threshold to prevent symptoms and suggests that subsequent systemic administration of low-dose PMO25 in SMA mice can provide therapeutic benefit and phenotypic rescue, presumably via peripheral SMN restoration. Our work also provides additional insight into the time window of response to administration of antisense oligonucleotides to SMA mice with an intermediate phenotype. This information is crucial at a time when a number of therapeutic interventions are in clinical trials in SMA patients.
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