MDA-supported researchers have developed compounds that block harmful interactions between a needed protein and abnormal RNA in cells with a type 2 myotonic dystrophy defect
MDA-supported investigators have designed two new compounds that precisely target the molecular defect that underlies type 2 myotonic muscular dystrophy (MMD2, or DM2), based on atomic-level imaging studies of the defect, also conducted in their laboratory.
MDA grantee Matthew Disney, an associate professor of chemistry at The Scripps Research Institute in Jupiter, Fla., and colleagues, published their findings online Dec. 16, 2013, in ACS Chemical Biology, where the full paper can be read without charge.
"We're highly encouraged by these results," said Jane Larkindale, MDA's vice president of research. "Therapeutics that are designed to limit the effects of specific gene mutations are becoming more common, and they're showing great promise in a number of MDA-covered diseases.This compound, the first targeting MMD2, shows a lot of promise and demonstrates the use of new technologies in finding mutation-specific therapeutics."
Expanded genetic material underlies MMD1, MMD2
MMD2 and the related type 1 myotonic muscular dystrophy (MMD1, or DM1), each result from abnormally expanded sections of DNA that disrupt the function of muscle and nerve cells, largely because they form toxic webs of protein-trapping genetic material in these cells.
In MMD1, the abnormal DNA expansion is composed of multiple "CTG repeats" — hundreds or thousands of repeating sequences of cytosine, thymine and guanine molecules in a gene called DMPK.
In MMD2, the abnormal DNA expansion is composed of multiple "CCTG repeats" — hundreds to thousands of repeating sequences of two cytosine molecules, a thymine and a guanine molecule, in a gene called ZNF9.
Despite having roots in different genes, the two MMD disorders are similar. Both cause abnormal accumulations of the genetic material RNA in cells, which traps and disables important cellular proteins. (When DNA is converted to RNA, thymine molecules are converted to uracil — "U" — molecules, so that the MMD2 RNA expansion is "CCUG" and the MMD1 RNA expansion is "CUG.")
Muscle weakness, difficulty relaxing muscles, cardiac abnormalities, gastrointestinal abnormalities, cataracts and excessive sleepiness can occur in both MMD1 and MMD2.
Freeing protein from expanded genetic material
Disney and other researchers have focused on developing MMD treatments by blocking the interaction of expanded RNA with proteins, particularly one called MBNL1. When MBNL1 is trapped by expanded RNA repeats, it can't perform crucial roles in cells, a phenomenon that appears to underlie many of the symptoms of MMD. An important goal of therapy development is freeing MBNL1 from this trap.
In 2012, Disney and his colleagues reported on MDA-supported research showing that their synthetic "H" compounds disrupted harmful interactions between expanded RNA and MBNL1 protein molecules in cells carrying the MMD1 genetic defect.
In their new publication, Disney and colleagues describe in never-before-seen detail the precise structure of the RNA expansion and details of the motion of this structure in cells carrying the MMD2 defect.
They then show how they designed compounds dubbed "2K-4" and "3K-4," which free MBNL1 protein molecules and improve the function of MMD2-affected cells.
"This is the first time that compounds have been demonstrated to affect MMD2 in cell culture models," said Disney. "Currently, we are focusing our efforts on further improving the potency of the compounds by using lessons we have learned in targeting MMD1 CUG repeat RNA, as well as planning animal studies when sufficient models become available. Once those studies are completed, we can plan better a course of action toward clinical trials."
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