Issue Date: July 20, 2009
RNA Distraction Is Therapeutic
When the human genome stutters by repeating sequences of three nucleotides, disease often follows. Researchers are now proposing to treat one such disease—a form of muscular dystrophy—by delivering complementary nucleotides that silence the stuttered sequences.
Affecting one in 8,000 people, myotonic dystrophy type 1 (DM1), is the most common form of adult-onset muscular dystrophy. DM1 causes muscle cells in the face, hands, and legs of adults to waste away. In many cases the disease also triggers an irregular heartbeat. But unlike Huntington's disease, which is caused by a toxic protein made from RNA that contains repeated stretches of three nucleotides, DM1 is caused by toxic RNA containing the stuttered sequences. In fact, the stretch of cytosine-uridine-guanine repeats is located in a part of the RNA that is normally not translated into a protein.
The troublesome, repetitive RNA forms a hairpin structure in the nucleus. This hairpin structure is irresistibly attractive to a protein called MBNL1, many molecules of which bind the RNA to form toxic aggregates. The binding of molecules of MBNL1 to the hairpin also prevents the RNA from being exported to the cytosol and translated into an important protein kinase.
With this in mind, Thurman M. Wheeler, Charles A. Thornton, and their colleagues at the University of Rochester came up with the idea to distract the toxic, repeated sections of RNA by means of a complementary sequence of so-called morpholino antisense nucleotides (Science 2009, 325, 336).
When they inserted the antisense sequence into mice with the muscular dystrophy, the therapeutic sequence of nucleotides blocked the harmful coupling of MBNL1 and the triplet sequence RNA and reduced many of the symptoms of DM1.
The work is "a highly significant advance," comments Stephen Tapscott, a biologist who studies the disease at the University of Washington School of Medicine. But he points out that like many oligonucleotide treatments, getting the remedy into the nucleus is a serious stumbling block.
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