Researchers at Baylor College of Medicine and Isis Pharmaceuticals have used a gapmer antisense-based strategy to destroy, in cultured cells and in mice, the genetic defect that causes type 1 myotonic muscular dystrophy (MMD1).

The gapmer antisense is designed to selectively target and destroy the genetic defect that causes MMD1 at the RNA level, rather than the DNA level. An expanded section of RNA in the gene for the DMPK protein, which is active in nerve and muscle cells, underlies MMD1. The expansion is made up of repeated sequences of three chemicals — cytosine, uracil and guanine — and is known as a CUG repeat expansion.

When the investigators injected the gapmer antisense into a leg muscle in mice with a CUG repeat expansion in their muscle fibers, they found it selectively destroyed the expanded RNA and corrected many aspects of cellular function in the mouse muscle tissue.

The gapmer antisense that the Cooper group developed attaches to the CUG repeats and then attracts an RNA-destroying enzyme called RNase H to them. RNase H is found in the nucleus of cells, which is where the CUG repeat expansion is located.

When the investigators combined the gapmer antisense with another strategy, known as a morpholino antisense, the results were even better. Morpholino antisense compounds directed at CUG repeats block this RNA, rather than destroying it. In doing so, they keep it from having harmful interactions with cellular proteins.

The researchers saw some muscle damage from the therapy, but they say they believe it is probably due to the delivery method they used in the mice, which will require some revision before it is tested in humans.

The findings have been published online in Proceedings of the National Academy of Sciences.

Release Date: Feb. 29, 2012
Source: Muscular Dystrophy Association