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Published on: May 11, 2018
Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models
Erkan Y Osman1, Madeline R Miller2, Kate L Robbins3
1Department 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.
Spinal muscular atrophy (SMA) therapeutics targeting Element 1 (E1) with antisense oligonucleotides (ASOs) show promise. E1(MO)-ASOs dramatically extend survival in severe and intermediate SMA mouse models by boosting functional SMN protein levels.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Spinal muscular atrophy (SMA) is a neurodegenerative disease resulting from SMN1 gene loss.
- SMN2, a near-identical copy gene, produces insufficient functional protein due to alternative splicing.
- Current therapeutic strategies often target SMN2 pre-mRNA splicing elements.
Purpose of the Study:
- To investigate the efficacy of targeting Element 1 (E1), an intronic repressor of SMN2 exon 7 splicing.
- To evaluate Morpholino-based antisense oligonucleotides (E1(MO)-ASOs) as a novel therapeutic approach for SMA.
Main Methods:
- Development and administration of E1(MO)-ASOs via intracerebroventricular injection.
- Assessment of SMN protein levels, survival rates, weight gain, and neuronal pathology in SMA mouse models (SMNΔ7 and SMN(RT)).
Main Results:
- A single E1(MO)-ASO dose in SMNΔ7 mice robustly induced SMN protein, extending mean lifespan from 13 to 54 days.
- Significant weight gain and correction of neuronal pathology were observed in treated SMNΔ7 mice.
- E1(MO)-ASO treatment in SMN(RT) mice extended lifespan by approximately 700% with weight gain comparable to unaffected animals.
Conclusions:
- Targeting the E1 repressor with ASOs represents a novel and effective therapeutic strategy for SMA.
- E1 ASOs significantly extend survival and improve disease phenotypes in pre-clinical SMA models.
- This approach offers a new molecular target for developing advanced SMA therapeutics.
