| First Author | Osman EY | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 18 | Pages | 4832-45 |
| PubMed ID | 24781211 | Mgi Jnum | J:213594 |
| Mgi Id | MGI:5585365 | Doi | 10.1093/hmg/ddu198 |
| Citation | Osman EY, et al. (2014) Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models. Hum Mol Genet 23(18):4832-45 |
| abstractText | 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 (SMNDelta7 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 approximately 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. |
