Systemic Versus CNS Delivery Of MOE Antisense Oligonucleotide to Correct Defective Splicing in a Severe Mouse Model of Spinal Muscular Atrophy

Krainer, A. R., Hua, Y. M., Sahashi, K., Rigo, F., Hung, G. N., Horev, G., Bennett, C. F. (October 2011) Systemic Versus CNS Delivery Of MOE Antisense Oligonucleotide to Correct Defective Splicing in a Severe Mouse Model of Spinal Muscular Atrophy. Nucleic Acid Therapeutics, 21 (5). A57-A57. ISSN 2159-3337

DOI: 10.1089/nat.2011.150


Spinal Muscular Atrophy (SMA) is a genetic disease characterized by progressive degeneration of motor neurons in the spinal cord, leading to muscle weakness and atrophy. SMA is caused by deletion or mutations in the Survival-of-motor neuron(SMN1) gene. The paralogous SMN2 gene, present in one or more copies in all SMA patients, attenuates SMA severity, but expresses low levels of full-length SMN protein, due to alternative splicing that results in inefficient inclusion of exon 7. Increasing SMN2 exon 7 inclusion to express more full-length, functional SMN protein in motor neurons is a promising approach to treat SMA. We previously reported a 2′-O-(2-methoxyethyl) (MOE) phosphorothioate 18mer antisense oligonucleotide (ASO) that targets a splicing-repressor binding site in intron 7. By preventing binding of the repressor (hnRNP A1), the ASO promotes efficient SMN2exon 7 inclusion in liver and kidneys of transgenic mice after systemic administration. It is generally believed that SMN restoration in spinal-cord motor neurons is necessary and sufficient to cure SMA. However, cardiac defects were recently reported in both severe SMA patients and mouse models. These defects might reflect autonomic dysfunction; alternatively, they could be caused by factors outside the CNS. In the latter scenario, peripheral SMN restoration might be necessary for therapy.We sought to compare the therapeutic effects of systemic restoration versus CNS restoration of the SMN protein in neonates of a severe mouse model (Smn-/-; hSmn2+/0) that survives 10 days. To increase SMN levels in the CNS, we directly injected the ASO into a cerebral lateral ventricle at postnatal day 1 (P1); to increase SMN levels in peripheral tissues, we subcutaneously injected the ASO into P0-P3 neonates. Surprisingly, neonatal systemic administration robustly rescued SMA mice, and was much more effective than intracerebroventricular administration alone; a single neonatal subcutaneous injection extended the median lifespan by 25-fold. The majority of the rescued mice had no motor defects, and showed increased motor-neuron numbers and normal neuromuscular-junction morphology. Remarkably, some of the SMA mice treated systemically at P0-P3 have so far survived for 1 year and are still vigorous. Our data not only demonstrate an effective drug candidate, but also reveal the importance of SMN restoration outside the CNS for treatment of severe SMA. The mechanisms underlying the striking effectiveness of SMN restoration in peripheral tissues will be discussed.

Item Type: Paper
Additional Information: Meeting Abstract
Subjects: Publication Type > Meeting Abstract
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide
diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matt Covey
Date: October 2011
Date Deposited: 11 Dec 2013 20:35
Last Modified: 28 Feb 2018 15:16

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