New Drug Combo Study Helps Push back Myotonic Dystrophy in Mice

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 Africian 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.

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.



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


Combination Drugs May be More Effective in Treating Myotonic Dystrophy

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., di erent 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 e ect [110]. Importantly, this combination treatment yielded lower toxicity and fewer o -target e ects 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.