Can manipulation of splicing offer gene therapy possibilities to those with tumour-prone disorders?

摘要

In this issue, Castellanos et al1 report the use of a mutation-specific antisense phosphorodiamidate morpholino oligomer to restore normal splicing and merlin protein levels in fibroblasts from a patient with neurofibromatosis type 2 (NF2). Although the researchers were not able to use the morpholino in vivo as the patient had died, this raises the real hope of correction of certain genetic abnormalities in tumour-prone disorders. Indeed, this would be the first 'true' gene therapy to treat such disorders as it would correct the deficient protein production associated with autosomal-dominant loss of function mutations in tumour-suppressor genes. The identification of deep intronic splicing mutations, which are only usually found after RNA analysis, allow the possibility to reverse the effect of such mutations by targeting the mutated sequence with specific antisense oligonucleotides (AONs). This is because the mutations do not alter coding DNA or the intron-exon splice sites. Furthermore, as 10 out of 17 NF2 exons are in-frame, this raises the possibility of skipping in-frame exons that contain a pathogenic mutation. However, for this to be effective, loss of the exon would have to show to be associated with some useful protein function in vivo.