MMD1: Synthetic 'H' Molecules Lock Up Toxic Repeats

Editor's note 3/15/12: This story was updated to reflect the availability of a podcast with Matthew Disney.

Small, laboratory-designed molecules can make a big difference in cells carrying the genetic defect that causes type 1 myotonic dystrophy (DM1, or MMD1), researchers have found.

Matthew Disney, Scripps Research Institute

Matthew Disney

(Photo courtesy: Scripps Research Institute)

The findings add to the therapeutic options being explored in MMD1, all of which target extra genetic material that interferes with the usual functioning of nerve and muscle cells in this disease.

MDA research grantee Matthew Disney, an associate professor in the Department of Chemistry at the Scripps Research Institute in Jupiter, Fla. ("Scripps Florida"), with colleagues there and at the University of Rochester (N.Y.), announced the findings online Feb. 14, 2012, in ACS Chemical Biology.

"Our group is centrally focused on answering fundamental questions about what types of drugs bind to what types of the genetic material known as RNA," Disney says.

"Our answers to this question so far have led us to target the MMD1 RNA with small molecules. We think this approach may be broadly applicable not only to MMD1 RNA but also to other RNA sequences that contribute to disease."

Expanded DNA and RNA root cause of MMD1

The underlying cause of MMD1 is an expanded section of the DNA sequence "CTG" (for cytosine, thymine, guanine) in a gene known as DMPK on chromosome 19. Normally, there are from three to 37 copies of this DNA "triplet repeat," while in MMD1, there can be hundreds or even thousands of such repeats.

When the DNA is converted to RNA (a normal cellular process), the expanded triplet repeats become "CUG" (for cytosine, uracil, guanine) instead of CTG.

Hundreds to thousands of extra CUG repeats in the RNA build up in the nuclei of nerve and muscle cells in MMD1, forming clumps of RNA and protein and disrupting cellular processes. These CUG repeat expansions have several effects:

  • The clumps they form, in conjunction with proteins, are probably harmful to cellular functions in and of themselves.
  • The extra CUG repeats stick to various cellular proteins, particularly one called MBNL1, trapping them and keeping them from doing their usual and important jobs.
  • The larger-than-normal pieces of RNA, containing the CUG repeat expansion, can't exit the nucleus, a necessary step for the RNA to be used for synthesis of the DMPK protein. Therefore, this protein is deficient in MMD1.

'H' compounds improved cellular functioning

The laboratory-synthesized compounds created by Disney's group consist of multiple copies of a bis-benzimidazole molecule, abbreviated as "H," separated by varying numbers of spacing modules, indicated by the numbers 2, 3 and 4. Each H component binds to a CUG repeat, with the spacers in between helping them to do so.

The nH-4 compounds, with varying number of H molecules and four spacer modules between each one, performed the best, improving the functioning of cells in a culture dish that had CUG repeat expansions. In summary, the nH-4 compounds:

  • disrupted the clumps of RNA and protein in cell nuclei;
  • improved a celluar process called splicing, probably by freeing the MBNL1 protein, a splicing protein, from its entrapment by CUG repeats; and
  • allowed RNA previously trapped in the nucleus to leave the nucleus and be used for protein synthesis.

Findings add to strategies to disrupt expanded RNA

The new findings add to previous experimental strategies developed to inhibit the effects of CUG repeat expansions in MMD1-affected cells.

In July 2009, researchers announced that a molecule known as CAG25 could perform this role in mice with an MMD1-like disease. CAG25 is an antisense oligonucleotide, a type of molecule that scientists are using experimentally to block, destroy or change genetic instructions in a variety of diseases.

In October 2009, MDA-supported researchers announced that a small molecule known as pentamidine could serve this function in mice with a disease resembling MMD1.

Other emerging strategies to treat MMD1 and type 2 myotonic dystrophy (DM2, or MMD2) were presented in December 2011 at the MDA-supported 8th International Myotonic Dystrophy Consortium. MMD2 is a similar disease to MMD1, but it's caused by an RNA repeat expansion on chromosome 3.

Learn more

A 13.5-minute podcast with Matthew Disney was posted at Quest Podcasts March 9, 2012.

To read more about MMD drug development by Disney's group, see Scripps Research Scientists Create Potent Molecules Aimed at Treating Muscular Dystrophy. This Feb. 22, 2012, news release from the Florida campus of the Scripps Research Institute refers to the findings published Feb. 14, 2012 (summarized above), as well as to the findings of Disney and others reported Feb. 2, 2012 ("Design of a Bioactive Small Molecule," referenced below).

Disney and colleagues have published the following other papers on drug development for MMD1 and MMD2:

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