title: Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy.
abstract: 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.
authors: Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, QE II Medical Centre, Perth, Western Australia.
authors: Chalermchai
authors: C
authors: Mitrpant
authors: Paul
authors: P
authors: Porensky
authors: Haiyan
authors: H
authors: Zhou
authors: Loren
authors: L
authors: Price
authors: Francesco
authors: F
authors: Muntoni
authors: Sue
authors: S
authors: Fletcher
authors: Steve D
authors: SD
authors: Wilton
authors: Arthur H M
authors: AH
authors: Burghes
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D015316:Genetic Therapy; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D060172:Morpholinos / Q000235:genetics*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D017186:Titrimetry; D014158:Transcription, Genetic
chemical_list: D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein
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