Cell biologists from the Radboud University Nijmegen Medical Centre (Nijmegen, the Netherlands) describe a new approach to remove the toxic agent that causes the neuromuscular disease myotonic dystrophy. Their findings are published in the scientific journal The Proceedings of the National Academy of Sciences.
Myotonic dystrophy, also called Steinert's disease, is a heritable, neuromuscular disease with an incidence of about one in 10,000. It is the most common muscular dystrophy in adults. Typical symptoms are delayed relaxation of muscles (myotonia) and muscle wasting (dystrophy). Other organs frequently involved in the disease are heart and brain. Currently, no cure is available. The Radboud University Nijmegen Medical Centre (RUNMC) is a reference centre for myotonic dystrophy in the Netherlands.
In 1992, researchers from the RUNMC were one of the groups who discovered the genetic cause of myotonic dystrophy. The disease is caused by an area in the DMPK gene that is larger than it should be. It was shown that the severity of the disease increases with the size of that expanded segment. DMPK RNA that is made as a copy of the expanded gene binds a number of important proteins in the cell and is subsequently trapped in the cell nucleus. As a result, cells, especially in muscle, heart and brain, will no longer function properly.
PhD student Susan Mulders, supervised by cell biologists Rick Wansink, PhD and Bé Wieringa, PhD designed a therapeutic strategy to slow or halt disease progression. She developed a highly effective method to neutralize DMPK toxic RNA and alleviate its detrimental effects in the cell. In collaboration with biotech company Prosensa, specialized in RNA-based therapeutics, Mulders used small artificial RNA molecules, called oligonucleotides, which bind to the toxic RNA. One particular oligonucleotide, specifically directed to the expanded area, was able to destroy the toxin in cells. This was first demonstrated in cultured cells from patients. In a second series of experiments mice with myotonic dystrophy were treated. Aggregates in cell nuclei disappeared and cell function improved.
Still a long way to therapy
There is still a long way to go before such an approach can be tested in patients, say the researchers, but these findings offer hope for the future. At the moment, oligonucleotide delivery to all cells in the mouse is being optimized. In addition, fundamental research needs to shine light on the oligo's working mechanism, which is still poorly defined.
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