Publikationsdatum:
2014-08-22
Beschreibung:
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 (SMN7 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.
Print ISSN:
0964-6906
Digitale ISSN:
1460-2083
Thema:
Biologie
,
Medizin
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