Antisense oligonucleotides—short segments of genetic material designed to target specific areas of a gene or chromosome—that activated an enzyme to “chew up” toxic RNA may point the way to a treatment for myotonic dystrophy, says researchers from Baylor College of Medicine and Isis Pharmaceuticals Inc.
“This is a proof-of-principle therapy that is effective in cell culture and mice,” says Thomas A. Cooper, MD, professor of pathology and immunology and molecular and cellular biology at Baylor College of Medicine. “The treatment will have to be refined to deliver systemically in people with myotonic dystrophy.”
Myotonic dystrophy occurs because of a mutation that causes numerous repeats of three letters of the genetic code (CTG) in a gene called DMPK. RNA is made as a step in the cell’s production of the protein associated with the gene. The messenger RNA that is produced from the mutated gene also contains the abnormal long repeats that cause the RNA to accumulate in the cell’s nucleus. There it sequesters and blocks the function of a Muscleblind-like 1 protein and activates another protein, CELF1. The proteins antagonize one another and the result is abnormal expression of proteins from many other genes in adult tissues, resulting in disease.
To counteract this, Cooper and his colleagues created gapmers (antisense oligonucleotides), that are strands of genetic material that seek out portions of the abnormal RNA repeats and target an RNase H enzyme to the toxic RNA, causing its degradation. They also showed that combining the gapmers with other antisense oligonucleotides that help released the sequestered Muscleblind-like1 can enhance the effect.
“It worked in cultures of cells with the expanded repeats and in mice that model myotonic dystrophy,” says Cooper. “We did it in skeletal muscle first because we can inject the material directly into the muscle.”
The researchers saw some muscle damage and inflammation in the animals they treated. Using the treatment in people will require more fine-tuning, says Cooper. He would like to be able to give the therapy systemically rather than directly into the muscle.
The research was reported in the Proceedings of the National Academy of Sciences.
Release Date: Feb. 27, 2012
Source: Baylor College of Medicine