HD Lighthouse Contributing Editor's Comment: Doctors Robert Ferrante and Rajiz Ratan, with multiple collaborators, are lead authors of the recent article which details neuroprotective benefits of the drug mithramycin as found in “Chemotherapy for the Brain” (November 17 Journal of Neuroscience). Their elegant long story briefly summarized: Mithramycin extended survival of the HD R6/2 mouse longer than any other agent so far described. Likewise it improved motor performance more than any other agent. And most importantly, brain changes usually present in the R6/2 mouse were so much improved they were “essentially absent”. Though the authors use “comparatively large effect” as their careful language, these combined results are much better than for any other agent so far studied.

And, though mithramycin is not an easy drug to work with, it is already FDA approved. And accordingly the authors make the argument that mithramycin should be among the top priorities for testing in patients.
--LaVonne Veatch Goodman, M.D.
Posted to the HDL: 25 Nov 2004

Chemotherapy for the Brain: The Antitumor Antibiotic Mithramycin Prolongs Survival in a Mouse Model of Huntington's Disease

Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. To identify the functional mechanism for the salubrious effects of mithramycin, we examined transcriptional dysfunction in R6/2 mice. Consistent with transcriptional repression playing a role in the pathogenesis of HD, we found increased methylation of lysine 9 in histone H3, a well established mechanism of gene silencing. Mithramycin treatment prevented the increase in H3 methylation observed in R6/2 mice, suggesting that the enhanced survival and neuroprotection might be attributable to the alleviation of repressed gene expression vital to neuronal function and survival. Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD. # # #

Source: J Neurosci. 2004 Nov 17;24(46):10335-10342

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