Correcting splicing in cancer: development of therapies based on targeted oligonucleotide enhancers of splicing
Many genetic diseases result from point mutations that prevent an exon being incorporated during pre-mRNA splicing. Changes in splicing patterns are beginning to be implicated also in acquired disorders, which is unsurprising since alternative splicing patterns account for three-quarters of the proteins expressed in mammals, including those that control cell life or differentiation. Hence, it was an important advance when we developed a method recently for rescuing the incorporation of defective or silent exons. In this method, RNA-binding splicing factors are recruited to a target exon using a bipartite oligoribonucleotide adaptor that contains a binding site for the factors and is complementary to the target RNA. The principle was tested with exon 7 of the SMN2 gene, which is defective in splicing but incorporation of which would rescue spinal muscular atrophy (SMA), one of the most common lethal autosomal recessive diseases. A bipartite oligoribonucleotide adaptor complementary to exon 7 stimulated splicing in vitro and rescued the incorporation of the exon and hence SMN protein expression in fibroblasts from patients. The method would have widespread applications if it could be developed to the point of clinical use.
The aim of the project is to optimise use of the method to control splicing reactions implicated in cancer development. You will optimise the design of the oligoribonucleotide measuring changes in RNA and protein levels in cultured cells, and you will join collaborative efforts with other labs to investigate ways of improving the uptake of oligos into cells and tissues.
We are an equal opportunities employer and particularly welcome applications for Ph.D. places from women, minority ethnic and other under-represented groups.
Skordis, L.A., Dunckley, M.G., Yue, B.-G., Eperon, I.C., and Muntoni, F. (2003). Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc. Natl Acad. Sci. USA 100, 4114-4119.
Reviewed in: http://www.nature.com/horizon/rna/background/splice.html