The RAS oncogenes are frequently mutated in human cancers. We have patented SSO technology targeting the RAS oncogenes as a potential new therapeutic approach towards several cancerous diseases. Germline mutations in HRAS cause Costello Syndrome, which is a congenital disease characterized by postnatal growth retardation, tumor predisposition, developmental delay, and abnormalities of the heart (cardiomyopathy), skin and skeletal muscles.
Initially based on an interest in a patient with Costello Syndrome, who had a much milder phenotype than expected based on the amino acid change, we discovered that mutations in HRAS exon 2 can decrease exon 2 splicing efficiency and RAS activity.
HRAS exon 2 often carries the transforming mutations in cancer. By targeting exonic splicing enhancer elements in HRAS exon 2 with SSOs we showed that we were able to induce exon 2 skipping and halt proliferation in cancer cells.
The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer Hartung et al., PLOS Genetics, May 2016
We have now expanded our strategy of splicing manipulation including also KRAS and NRAS oncogenes. We work in cell cultures with SSO-based manipulation of splicing and use a range of assays such as Incucyte proliferation measurements and WST-1 cell viability assay.