Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular AtrophyReportar como inadecuado




Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Spinal muscular atrophy SMA is caused by loss of the Survival Motor Neuron 1 SMN1 gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene or genes that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides PMO that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.



Autor: Chalermchai Mitrpant , Paul Porensky, Haiyan Zhou, Loren Price, Francesco Muntoni, Sue Fletcher, Steve D. Wilton, Arthur H. M. Bu

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados