Tag Archives: treament

New study suggests gout drug, colchcine, may help treat Myotonic Dystrophy DM1 in future

Posted on by
Reply

A new study by several major researchers in the myotonic dystrophy field had a very interesting study that identified a FDA approved drug that may help with myotonic dystrophy.  However, as usual, more research is needed to validate the approach. The study identified and validated a cell based assay screening tool that enabled the researchers to look at a number of drugs. The most promising drugs were colchicine, thiocolchcine,suprafenacine, amsacrine, azathioprine, The researchers decided to concentrate on was Colchicine an already approved FDA drug for gout and familial Mediterranean fever (FMF), 

“We primarily focused on colchicine because it is an inexpensive, FDA-approved, natural therapeutic that is generally well tolerated and is currently used in the clinic to treat gout and familial mediterranean fever (FMF)“‘

The next step the researchers took was to use colchicine in mice that had been altered to have myotonic dystrophy. The drug was injected into these mice. The researchers found that the amount of mutant RNA was decreased in  the muscle cells.

“Collectively, these data demonstrate that microtuble inhibition in vivo leads to a selective reduction in expanded CUG RNA levels without broadly affecting the transcriptome”

Next the researchers tested colchicine in patient cells with myotonic dystrophy. They selected patients cells with a repeat count of 1900-3000 repeats. The results were positive

“we observed significant rescue of missplicing”

OVERALL DISCUSSION

The researchers established a cell line that enabled them to screen a large number of compounds that might help to reduce DM1 in theory. They found a list of candidates and then selected colchicine as a drug to model

“We then validated the use of a microtubule inhibitor in the HSA DM1 mouse model and in DM1 patient cells with colchicine an FDA approve natural microtubule inhibitor currently used in the clinic. Our results provide proof of principle for the identification of compounds and cellular targets selectively modulater r(CUG)exp levels in DM1 using cell-based screening.

Our Observation of a partial rescue in DM1 relevant missplicing in multiple models warrants further evaluation of colchicine. The study is NOT sufficient to address the therapeutic efficacy of colchicine or of general microtuble inhibition in the treatment of DM1, It is important to determine if there is a positive trade off between the therapeutic efficacy in reducing DM1 symptoms in  relation to known toxicity from microtuble inhibition. As an example, and although very rare, myopathy has been reported in some individuals with compromised renal function who had been treated chronically with colchicine for gout. Future Long term treatment in DM1 animal models such as HSA at clinical doses to evaluate the reversal of DM1 phenotypes are a [prerequisite to determine if any clinical studies are warranted”

Overall this is a promising approach that needs more study. However, for those in the end stages of Myotonic dytrophy disease this may be something to discuss with your medical staff.

 

 

 

NOTE:  Transcriptome definition – Wikipedia

https://en.wikipedia.org/wiki/Transcriptome
The transcriptome can be seen as a subset of the proteome, that is, the entire set of proteins expressed by a genome.. However, the analysis of relative mRNA expression levels can be complicated by the fact that relatively small changes in mRNA expression can produce large changes in the total amount of the corresponding protein present in the cell.

 

 

colchicine-Study

PDF Embedder requires a url attribute

Press Release about Cugamycin that might treat Myotonic Dystrophy in Future

Posted on by
Reply
PUBLIC RELEASE: 

New therapy targets cause of adult-onset muscular dystrophy

Animal study shows no off-target effects of RNA-based therapy

SCRIPPS RESEARCH INSTITUTE

 
IMAGE

IMAGE: SCRIPPS RESEARCH GRADUATE STUDENT ANGEL ANGELBELLO AND CHEMISTRY PROFESSOR MATTHEW D. DISNEY, PHD, REPORT PROMISING DATA ABOUT THEIR RNA-BINDING MYOTONIC DYSTROPHY TYPE 1 COMPOUND IN PNAS. view more 

CREDIT: SCRIPPS RESEARCH

JUPITER, Fla. – April 1, 2019 — People diagnosed with myotonic dystrophy type 1 have difficulty unclenching muscles due to a genetic defect that generates toxic material within their cells. There is currently no treatment. In a new report published in the Proceedings of the National Academy of Sciences on Monday, a group at Scripps Research in Florida reports making a potential drug that targets its key disease-causing RNA. In mouse and cellular models of myotonic dystrophy type 1, it improved the muscle defects with no apparent side-effects.

The study appeared on line Friday in PNAS. More work lies ahead before testing in people will be possible, but “the results look better than we could have imagined,” says lead author Matthew Disney, PhD, a Scripps Research chemistry professor.

“The results suggest that our technology can be used to treat myotonic dystrophy type 1 and similar categories of inherited diseases, and without unintended, off-target effects,” Disney says, adding, “There is great potential for drugging RNA in all disease settings.”

The most common form of muscular dystrophy in adults, myotonic dystrophy type 1 has been estimated to affect around 1 in 8,000 people, although the Myotonic Dystrophy Foundation, based in San Francisco, reports that misdiagnosis is common, likely leading to underreporting. Genetic studies suggest the actual numbers are more than three times higher, around 1 in 2,500, says Molly White, CEO of the foundation.

The disease is inherited. Symptoms emerge in late teens or early adulthood as genetic changes accumulate. They include muscle clenching, lock-jaw, early-onset cataracts, brain fog, muscle wasting and weakness, digestive difficulties, and sudden cardiac death, White says. Severity and rate of progression depend on factors including the nature of the genetic defect.

Myotonic dystrophy type 1 occurs when a sequence of three nucleotides, CTG, is repeated too many times within a gene called DMPK. Toxic protein clumps generate further genetic defects, resulting in muscle weakness and other symptoms. A healthy person could carry between 5 and 35 repeats of CTG within that gene without experiencing obvious difficulty. But symptomatic people may have 50, 100 or even up to 4,000 repeats of the CTG sequence.

The drug Disney’s group designed, called Cugamycin, works by recognizing the toxic RNA repeats and destroying the garbled gene transcript. Significantly, in treated animals, the drug left the healthy version of the gene transcript intact. The results were consistent in both the mouse model of myotonic dystrophy type 1 and in human patient-derived muscle fibers called myotubes.

Cugamycin was made by attaching an RNA-binding molecule to an existing drug called bleomycin, which cleaves nucleic acids.

“Analysis of the tissue from a pre-clinical disease model showed more than 98 percent of the disease defects are improved, with no detectable off-targets.” Disney says.

So far, the results have been excellent, but these studies are still in their early stages, says Alicia Angelbello, the study’s first author and a Scripps Research graduate student.

“A key next question will be to evaluate the effectiveness of our compound over a longer period of time,” she adds. In the current study, the treated mice experienced fewer instances of “myotonic discharges” in their muscles–occasions when it takes longer than usual for a contracted muscle to relax–compared to untreated mice, Angelbello says.

“Once given the Cugamycin at a dose of 10 milligrams per kilogram, the frequency of the myotonic discharges was reduced by 50 percent, which is a significant improvement,” Angelbello says. “The fact that we can improve the muscular and genetic defects in DM1 mice with the molecules we have made in the lab is a significant step in learning about how to treat this disease,” she says. The Myotonic Dystrophy Foundation has supported Disney’s work for many years.

“Matt Disney is super-committed to making a treatment for this disease,” says White, CEO of the Myotonic Dystrophy Foundation. “It’s clear that many people think his lab is on the right track. We’re thrilled at the progress he is making.”

###

In addition to Disney and Angelbello, the authors of the study, “Precise small molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model,” include Suzanne Rzuczek, Jonathan Chen and Michael Cameron of Scripps Research; Kendra McKee, Hailey Olafson and Eric Wang of the University of Florida; and Walter Moss of Iowa State University. Disney and Wang consult for Expansion Therapeutics. Rzuczek is an employee of Expansion Therapeutics. Disney’s work was funded by the National Institutes of Health (grant DP1NS096898) and the Muscular Dystrophy Association (grant 380467). The Myotonic Dystrophy Foundation also provided support.