PT  - JOURNAL ARTICLE
AU  - Tristan H. Coady
AU  - Christian L. Lorson
TI  - <em>Trans</em>-Splicing-Mediated Improvement in a Severe Mouse Model of Spinal Muscular Atrophy
AID  - 10.1523/JNEUROSCI.4489-09.2010
DP  - 2010 Jan 06
TA  - The Journal of Neuroscience
PG  - 126--130
VI  - 30
IP  - 1
4099  - http://www.jneurosci.org/content/30/1/126.short
4100  - http://www.jneurosci.org/content/30/1/126.full
SO  - J. Neurosci.2010 Jan 06; 30
AB  - Spinal muscular atrophy is a leading genetic cause of infantile death and occurs in ∼1/6000 live births. SMA is caused by the loss of Survival Motor Neuron-1 (SMN1), however, all patients retain at least one copy of a nearly identical gene called SMN2. While SMN2 and SMN1 are comprised of identical coding sequences, the majority of SMN2 transcripts are alternatively spliced, encoding a truncated protein that is unstable and nonfunctional. Considerable effort has focused upon modulating the SMN2 alternative splicing event since this would produce more wild-type protein. Recently we reported the development of an optimized trans-splicing system that involved the coexpression of a SMN2 trans-splicing RNA and an antisense RNA that blocks a downstream splice site in SMN2 pre-mRNA. Here, we demonstrate that in vivo delivery of the optimized trans-splicing vector increases an important SMN-dependent activity, snRNP assembly, in disease-relevant tissue in the SMA mouse model. A single injection of the vector into the intracerebral-ventricular space in SMA neonates also lessens the severity of the SMA phenotype in a severe SMA mouse model, extending survival ∼70%. Collectively, these results provide the first in vivo demonstration that SMN2 trans-splicing leads to a lessening of the severity of the SMA phenotype and provide evidence for the power of this strategy for reprogramming genetic diseases at the pre-mRNA level.