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Oligonucleotides are compounds used by scientists seeking to repair the deficient genetic code in the dystrophin gene. Unlike traditional gene therapy approaches, scientists are not attempting to replace the genetic code; instead, they want the muscle cell to ignore the defective part of the dystrophin gene and make a smaller (but fully intact) version of dystrophin. This research strategy is known as exon-skipping.
The intended result is that the boy’s muscle cell will then produce dystrophin on its own. Scientists working with oligonucleotides hope to use a drug to “unzip” the genetic code, and then shift one side of the code to the right by a tiny degree, thereby giving the cell enough code to produce a viable dystrophin protein.
Scientists believe that this therapy could, for example, change the reading frame of a deletion in the dystrophin gene, so that an out-of-frame deletion in the dystrophin gene could be transformed into an in-frame deletion.
Their hope is that this change would cause the muscle cell to produce a form of dystrophin that is at least partially functional, which could result in a significant improvement in the quality of life for a boy with Duchenne, essentially converting his symptoms to those of the less debilitating Becker muscular dystrophy.
There remain, unfortunately, two major drawbacks to oligonucleotide therapy. First, scientists have encountered the same systemic delivery problems encountered in devising gene therapy strategies. Second, the effects of oligonucleotides wear off quickly (in only a matter of weeks), so subjects would need to repeat the oligonucleotide therapy frequently.
The status of exon-skipping
For a review of the current status of exon-skipping, read Dr. Guenter Scheuebrandt’s Interview with Dr. Annimieke Aartsma-Rus (PDF).