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Hum Mol Genet. 2014 Sep 15;23(18):4832-45. doi: 10.1093/hmg/ddu198. Epub 2014 Apr 29.

Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models.

Author information

1
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65211, USA, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
2
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA, Genetics Area Program, Christopher S. Bond Life Sciences Center Room 403, University of Missouri, Columbia, MO 65211, USA and.
3
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
4
College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
5
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65211, USA, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA, Genetics Area Program, Christopher S. Bond Life Sciences Center Room 403, University of Missouri, Columbia, MO 65211, USA and lorsonc@missouri.edu.

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of Survival Motor Neuron-1 (SMN1). In all SMA patients, a nearly identical copy gene called SMN2 is present, which produces low levels of functional protein owing to an alternative splicing event. To prevent exon-skipping, we have targeted an intronic repressor, Element1 (E1), located upstream of SMN2 exon 7 using Morpholino-based antisense oligonucleotides (E1(MO)-ASOs). A single intracerebroventricular injection in the relatively severe mouse model of SMA (SMNΔ7 mouse model) elicited a robust induction of SMN protein, and mean life span was extended from an average survival of 13 to 54 days following a single dose, consistent with large weight gains and a correction of the neuronal pathology. Additionally, E1(MO)-ASO treatment in an intermediate SMA mouse (SMN(RT) mouse model) significantly extended life span by ∼700% and weight gain was comparable with the unaffected animals. While a number of experimental therapeutics have targeted the ISS-N1 element of SMN2 pre-mRNA, the development of E1 ASOs provides a new molecular target for SMA therapeutics that dramatically extends survival in two important pre-clinical models of disease.

PMID:
24781211
PMCID:
PMC4140465
DOI:
10.1093/hmg/ddu198
[Indexed for MEDLINE]
Free PMC Article

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