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

Posted on January 8, 2020 by super_admin

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

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New Drug Combo Study Helps Push back Myotonic Dystrophy in Mice

Posted on August 24, 2019 by super_admin

A recently published article used a combination of erythromycin and the prodrug of furamidine (pafuramidine) orally administed to mice that had Myotonic Dystrophy. This combination help with the problems that DM causes in the cells. A promising potential therapy however with some limitations.

Already a study back in 2014 showed that Erythromycin an FDA approved drug can help with a therapeutic approach to the disease in Mice. Many individuals have also taken this FDA approved drug to help with the myotonic dystrophy disease.

The new combination involves combination of erythromycin and the prodrug of furamidine (pafuramidine), The second drug pafuramidine is not available yet. It was studied in a phase III study for African sleeping sickness but not easily commercially available. The drug was found effective for African Sleeping sickenss. It looked very promising with a phase 3 study in many countries in Africa. However, the phase I testing in healthy volunteers there was a possible adverse reaction to pafuramidine casing renal issues in 2 of 175 healthy volunteers (1.1%) . Looking more deeply into the adverse reaction there were 2 individuals with serious reactions including one that required dialysis as a probably result of the drug pafuramidine. As such the drug was not further pursed. In the study in Mice with myotonic dystrophy the amount of pafuramidine was 5X lower than what was used in humans for African sleeping sickness so potentially much safer. There is some research into other analogs (Variations) of pafuramidine for future studies.

Th study still shows that erythromycin can be potentiated (enhanced) by other drugs but this combo seems to dangerous to use in humans due to the kidney reactions in a small group. Its small but the drug seemed to seriously degrade the urinary system

Here is some information on the study:

In DM1 patient-derived myotubes, the rescue of mis-splicing was observed with little to no celltoxicity. In a DM1 mouse model, a combination of erythromycin and the prodrug of furamidine (pafuramidine), administered orally, displayed both additive and synergistic mis-splicing rescue. Gene expression was only modestly affected, and over 40% of
the genes showing significant expression changes were rescued back toward WT expression levels. Further, the combination treatment partially rescued the myotonia phenotype in the DM1 mouse. This combination treatment showed a high degree of
mis-splicing rescue coupled with low off-target gene expression changes. These results indicate that combination therapies are a promising therapeutic approach for DM1. But the exact Drug pafuraminde has a severe adverse reaction so it can not be used now. Perhaps other drugs that potentiate erythromycin can be used in the future.

Combination-Therapy-Erythromycin-and-Furamidine

Below is the supporting information including the instructions for making the second drug pafurmidine

Synthesis-scheme-for-pafuramidine-manufacturing

Combination Drugs May be More Effective in Treating Myotonic Dystrophy

Posted on August 23, 2019 by super_admin

A recent review study suggested that combination therapies may be the most optimal pathway to treat myotonic dystrophy. A few years ago when the defective pathway for myotonic dystrophy was identified it was proposed that treatment would be easy to find as it was proposed that the clumping would be easy to defeat. This has proven not to be the case. Here is a summary from the study:

One potential strategy is a combination approach (e.g., dierent small molecule
combinations, small molecules plus ASOs, transcription inhibition plus RAN protein ablation, etc.)targeting multiple processes and allowing synergy in disease modulation. As proof of concept, a recent study reported that two previously characterized compounds that separately displayed ecacyin DM1 models, furamidine and erythromycin, displayed an even greater rescue of mis-splicing in
combination than expected from a mere additive eect [110]. Importantly, this combination treatment yielded lower toxicity and fewer o-target eects than when either drug was administered alone inDM1 patient and mouse models [110]. Hence, if combination treatments are a viable therapeutic strategy for treating DM, there are already many unexplored therapeutic avenues that could potentially hold promise. Given the number of small molecule therapies for DM on the horizon, it will be exciting
to follow their development. These studies will lay the groundwork for the eventual therapies for treating DM and will likely illuminate disease biology and treatment avenues for other microsatellite expansion disorders involving toxic RNA mechanisms.

Review-of-Drug-Therapies-for-myotonic-Dystrophy

MDA Invests 550K into San Diego Therapy Company

Posted on July 24, 2019 by super_admin

MDA Awards Locana $550K to Advance Potential RNA-targeting Therapy for Myotonic Dystrophy

July 8, 2019

by Mary Chapman

In News.

MDA Awards Locana $550K to Advance Potential RNA-targeting Therapy for Myotonic Dystrophy

The Muscular Dystrophy Association (MDA) has awarded Locana $550,000 through its MDA Venture Philanthropy (MVP) program to help advance the biotech company’s therapy platform for myotonic dystrophy (DM).

Specifically, the grant to the San Diego, California-based gene therapy company is aimed at furthering the development of its RNA-targeting technology.

“We’ve witnessed incredible innovation with the development of the first FDA-approved gene therapy for a neuromuscular disease,” Lynn O’Connor Vos, the MDA’s president and chief executive officer, said in a news release. She was speaking in reference to Zolgensma (AveXis and Novartis), approved May 24 by the U.S. Food and Drug Administration to treat spinal muscular atrophy.

“This gives us hope that novel approaches — such as Locana’s for designing highly specific RNA-targeting candidates — for treatment of myotonic dystrophy can address the significant unmet needs for patients who live with this genetic disease.”

The project’s chief investigator will be Ranjan Batra, Locana’s vice president of research and development.

“We appreciate the support of MDA to address this devastating disease,” said Jeffrey M. Ostrove, PhD, Locana chief executive officer. “DM is caused by expression of dysfunctional, repetitive RNA in diseased tissues, where application of Locana’s core RNA-targeting technology has been shown to have potential for single-dose benefit, and could provide a long-lasting approach for patients.”

Estimated to affect one in 8,000 individuals globally, myotonic dystrophy is the most common adult-onset form of muscular dystrophy (MD) and has two types, both caused by genetic mutations. DM1 results from an abnormal expansion in a region of the DMPK gene. DM2 is caused by an expansion in the CNBP gene.

Locana is using its gene-editing CRISPR/Cas9 technology to target disorders, including DM and Huntington’s disease, caused by abnormally repeated genetic sequences.

With this monetary support, the MDA is hoping to build upon work detailed in proof-of-concept studies published the journal Cell in 2017. Those efforts involved researchers, including founding officers of Locana, that used CRISPR to edit RNA originating from mutations responsible for myotonic dystrophy. Scientists were able to successfully edit the faulty RNA in muscle cells of those with DM and related diseases, as well as reverse hallmark features of disease.

Producing RNA-targeting molecules could lead to enduring effects, the company said. That means the therapy might need to be administered just once.

The strategy is distinct from DNA-targeted approaches, as well as from nucleic acid-based RNA targeting. Its overarching goal is to produce a portfolio of treatments that address the primary cause of genetic diseases caused by the actions of dysfunctional RNA.

“Mutations in our DNA can cause disease, and our RNA-targeting technology platform allows us to precisely address these mutations,” Locana states on its website. “By targeting RNA, our approach avoids the risk of off-target effects in DNA.”

MVP, the MDA’s drug development program, is solely focused on funding the discovery and clinical application of treatments and cures for neuromuscular diseases.

Myotonic Dystrophy Researcher Receives Award

Posted on May 22, 2019 by super_admin

https://news.illinois.edu/view/6367/787310

Images
- The Barry M. Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Goldwater, who served 30 years in the U.S. Senate.

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CHAMPAIGN, Ill. — University of Illinois student Philip Kocheril was awarded a Barry M. Goldwater scholarship for the 2019-20 and 2020-21 academic years in recognition for his potential to contribute to the advancement of research in the natural sciences, mathematics or engineering.

The Barry M. Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Goldwater, who served 30 years in the U.S. Senate. The program encourages the continued development of highly qualified scientists, mathematicians and engineers by awarding scholarships to sophomores and juniors from the U.S. who intend to pursue doctorates. The scholarship provides recipients $7,500 annually for tuition, fees, books or room and board.

Philip Kocheril, of Champaign, a third-year chemistry major at Illinois, was awarded a Barry M. Goldwater scholarship in recognition for his potential to contribute to the advancement of research in the natural sciences, mathematics or engineering.

Photo provided

This year’s 496 Goldwater Scholars were selected on the basis of their demonstrated leadership and academic promise in the fields of science or engineering. The Goldwater Foundation doubled the number of grantees this year as the result of a partnership with the Department of Defense National Defense Education Programs. Over 5,000 students across the country submitted applications, of which 1,223 mathematics, science and engineering students were nominated by the faculties of colleges and universities nationwide.

According to David Schug, the director of the National and International Scholarships Program at Illinois, “Our campus committee unanimously and enthusiastically endorsed Phil based on his proven initiative, deep research experiences – resulting in first- and second-authored publications and national presentations – and extraordinary letters of support.”

Kocheril, of Champaign, is a third-year chemistry major with a minor in music. He aspires to obtain a Ph.D. in chemistry and conduct research in a university setting. While attending Champaign Centennial High School, Kocheril worked with former U. of I. professor Benjamin McCall performing mid-infrared spectroscopy on molecular ions found in the interstellar medium. In fall 2018, he joined the drug-discovery project of professor Steven Zimmerman and designed, synthesized and modeled potential small molecule therapeutics for myotonic dystrophy.

Kocheril is a member of both the Campus Honors Program and the James Scholar Honors program at Illinois, with a perfect 4.0 GPA. An avid musician, Kocheril is a member of professor Tito Carrillo’s jazz trumpet studio, and he composes and performs jazz with numerous ensembles.

Editor’s note: For more information, contact David Schug, National and International Scholarships Program director, 217-333-4710, email topscholars@illinois.edu

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