Therapeutic approaches to treat human spliceosomal diseases.

Mutated RNA splicing machinery drives many human diseases and is a promising therapeutic target for engineering and small molecule therapy. In the case of mutations in individual genes that cause them to be incorrectly spliced, engineered splicing factors can be introduced to correct splicing of these aberrant transcripts and reduce the effects of the disease phenotype. Mutations that occur in certain splicing factor genes themselves have been implicated in many cancers, particularly myelodysplastic syndromes. Small molecules that target splicing factors have been developed as therapies to preferentially induce apoptosis in these cancer cells. Specifically, drugs targeting the splicing factor SF3B1 have led to recent clinical trials. Here, we review the role of alternative splicing in disease, approaches to rescue incorrect splicing using engineered splicing factors, and small molecule splicing inhibitors developed to treat hematological cancers.