As many as half of the disease-associated single-nucleotide mutations in the coding regions of genes affect RNA splicing. Often, such mutations result in the exclusion of exons from mRNA, a process known as exon skipping. So, finding a way to reinstate these exons into the transcript could be an effective route to treating the underlying cause of a wide range of diseases.

Adrian Krainer and Luca Cartegni now describe the development of ESSENCE (exon-specific silencing enhancement by small chimeric effectors), which can correct these genetic typos by emulating the function of essential splicing factors called serine/arginine-rich (SR) proteins. SR proteins work by binding to exonic splicing enhancers (ESEs) and recruiting the cutting-and-pasting components of the splicing machinery through protein–protein interactions mediated by an RS domain (a domain characterized by several Arg–Ser dipeptides).

To restore normal splicing in exon-skipping models, Krainer and Cartegni fused a synthetic RS domain to an antisense fragment that binds to specific exons. They tested the ESSENCE concept first in the breast cancer 1, early onset gene (BRCA1), in which a natural mutation in an ESE in exon 18 causes exon skipping. The addition of an ESSENCE compound with the exon-18-specific antisense fragment restored accurate splicing in vitro, and required both the antisense-targeting fragment and the synthesized RS-protein-recruitment domain.

The authors then looked at one of the best-characterized examples of an ESE associated with disease: spinal muscular atrophy (SMA), a paediatric neurodegenerative disorder caused by the loss of both functional copies of the survival of motor neuron 1 (SMN1) gene. SMN1 could be compensated by SMN2— a related gene product — but a single-nucleotide mutation in exon 7 of SMN2 produces a defective isoform that lacks this exon. The authors showed that creating an ESSENCE compound that targets this mutation restored the inclusion of exon 7 in the transcript in vitro. The technique is being developed to optimize in vivo delivery and activity, with the hope that the next generation of ESSENCE compounds will represent a viable approach for the treatment of SMA and many other genetic diseases.