Many genetic diseases result from a small lapse: Cells ignore some sections of genes that encode protein. In the 13 January issue of Nature Structural Biology, Luca Cartegni and Adrian Krainer of New York's Cold Spring Harbor Laboratory describe a small molecule they've designed that prevents such mistakes. Test tube experiments suggest that the strategy may one day offer a novel route for treatment of these diseases.
The genetic instructions for making a protein in multicelled organisms such as humans aren't straightforward. Our genes are mosaics of protein-encoding DNA sections, called exons, separated by noncoding DNA. Cells first make an RNA copy of the DNA, then splice the exons together to form the final RNA template. To help guarantee correct splicing, short sequences within the exon RNA called ESEs--for exonic splicing enhancers--get tagged by so-called SR proteins. The tag fastens the exon to the molecular machinery responsible for splicing. If a mutation disrupts the ESE sequence, SR can't bind to it, and the exon gets left out of the RNA template.
To solve this problem, Cartegni and Krainer designed a hybrid molecule. At one end is an RNA-like tail designed to target the skipped exon; at the other end is a short string of amino acids, like those of SR for grabbing the splicing machinery.
As a prototype effort, Cartegni and Krainer designed the RNA-like end to bind the exon skipped in the mutant breast cancer gene BRCA1. Mixing labeled RNA copies of the defective gene with cell extracts produces spliced BRCA1 RNA templates that are one exon short. But even a pinch of the hybrid molecule allowed the mutant gene to generate the full-length RNA template, with all exons accounted for. The investigators then designed another hybrid molecule to target the skipped exon of SMN2, a gene involved in spinal muscular atrophy, and they had similar success.
Cartegni and Krainer's hybrid molecule is "an ingenious tool" that could have widespread clinical applications, says Ryszard Kole of the University of North Carolina, Chapel Hill. The next critical step, according to Kole, is to show that these molecules can be delivered into the cells and, more importantly, into living organisms.