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Apr
16

Landmark study on fibromuscular dysplasia may point to potential treatments

Nearly two months ago I wrote briefly about the rare disease fibromuscular dysplasia (FMD) for which there has been virtually no information on disease mechanism published for 40 years. Yesterday Sarah Kucharski (FMD Chat, CEO/Chairman & Founder) pointed me to a brand new paper from Dr. Nazli McDonnell et al (National Inst of Aging) . Having read it I will summarize what stood out for me at least.

The authors studied 47 patients with FMD. 95.7% had degenerative disk disease and “95.7% had greater or equal to 4 features associated with other genetically mediated connective tissue disorders with vascular abnormalities”. This suggests FMD is similar to some other diseases. While the underlying molecular defects are unknown, they also looked at biomarkers in patient derived fibroblasts and showed that transforming growth factor, TGF-β1 was significantly elevated in fibroblasts and plasma. TGF-β signalling seemed key although increased expression may not be a primary defect…but what if it is a viable target, what can be done?

What drugs down regulate TGF-β1 ? Well it seems like there is no shortage  – (click on each of the following names to highlight recent papers in PubMed) – angiotensin inhibitors like Losartan, telmisartan; retinoic acid; Statins like pitavastatin and rosuvastatin ;  antibiotics anisomycin (ANS) and puromycin (PURO) ; NSAIDS like tolfenamic acid, the cannibinoid (CB1) antagonist rimonabant.. The renin inhibitor Aliskiren may be useful, heck even thalidomide may be worth studying.

So there are many classes of compounds that could be clinically accessible to these patients. As there appears to be no animal model of the disease, perhaps the proposal of clinical studies looking at different classes of compounds with effects on inflammatory cytokines would be worthwhile. Endpoints would be inhibition of these cytokines and impact on histopathology? A head to head comparison in patient fibroblasts could be a first step, this may be cheaper and at least point to the most interesting compounds in each class. Of course differences in ADME/Tox properties will be important as well as any side effects which could exacerbate the disease.

So the big question is why was this work published in the FASEB Journal (impact factor 5.7) and not a clinical journal like the Journal of clinical investigation (impact factor 12.8) which would have also had greater visibility for clinicians?

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