HD Lighthouse Contributing Editor's Comment: In April 2006, veteran researcher R. Ferrante and collaborators reported results from a thorough and significant study of CoQ-10 “Dose ranging and efficacy study of high-dose coenzyme Q-10 formulations in Huntington’s disease mice” (Biochem Biophys Acta. 2006 Apr 17)). In this article, the authors find that more is better. The HD mice treated with high dose CoQ-10 had survival benefit of 25.3%, which is significantly higher than 13-14.5% benefit shown in earlier studies using lower doses. (Ferrante 2002, 2005).

The authors also show that the levels of CoQ-10 and ATP (the major energy molecule for all cells) are lower in the HD mouse than the normal mouse, and that high dose CoQ-10 brings the levels of both of these molecules back to normal. And, as was previously reported for creatine, high dose CoQ-10 decreases OH8dG, the biomarker for oxidative DNA damage, in both urine and brain.

The authors also report on the difference in bioavalability (or how much product is absorbed into bloodstream) for two CoQ-10 products. They show that one of the products (Tishcon) is absorbed 5 times better than the other (Chemco). In other words, 5 times as much Chemco product must be taken by mouth to get the same CoQ-10 blood level that the Tishcon product gives. Of interest, the Vitaline product was not compared (private communication Dr. R. Ferrante). However, Tishcon reports higher bioavailabily (by more than a factor of 2) than Vitaline (private communication).

So what does this mean to the HD patient community?

In the near future, both Coenzyme Q-10 and creatine will go forward for study in separate Huntington Study Group (HSG) trials funded by NIH. There is significant evidence that both are worthy to go forward to phase III human study.

The Huntington’s community has hope that both of these trials will be successful. But assuming there is success; let’s go the next step. These two separate trials will overlap in time. What happens if one is deemed successful before the other? Will the first agent be added to the second trial (as is ethically required) even though it greatly complicates analysis of results? What happens if both creatine and CoQ-10 (both target bioenergetics) are deemed successful at the same time? Will medical experts recommend one over the other, or will they recommend both?

It’s apparent that the next step gets complicated. and it gets expensive if a third trial follows that will combine the two.

During this past year, we at the Lighthouse promoted a single “combinations” clinical trial that could test creatine and CoQ-10 separately and in combination. We were told that this would be too complicated, cost too much, and require too many participants compared to single agent trials. Now we have two separate trials, that will likely call for another expensive trial that will need yet more participants to answer combination benefit.

Doesn’t sound less expensive to me. And of great importance to HD people, single sequential trials will take more time than some of us have. When will this cost, measured in human years, become part of the HSG equation?

References:

• Smith, K. M., Matson, S., Matson. W.R., Cormier, C., Del Signore, S. J., Hagerty, S. W., Stack, E. C., Ryu, and R. J. Ferrante. "Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice." Biochimica et Biophysica Acta 2006 Apr 17 (Epub ahead of print)
• Ferrante, R. J., O. A. Andreassen, A. Dedeoglu, K. L. Ferrante, B. G. Jenkins, S. M. Hersch and M. F. Beal (2002). "Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease." J Neurosci Mar 1;22(5):1592-9.
• Stack E.C., Smith K.M, Ryu H, Cormier K, Chen M, Hagerty SW, Del Signore SJ, Cudkowicz ME, Friedlander RM, and Ferrante RJ.

-- LaVonne Veatch Goodman, M.D.
Posted to the HDL: 05 Jun 2006

Dose ranging and efficacy study of high-dose coenzyme Q(10) formulations in Huntington's disease mice.

K Smith, S Matson, W Matson, K Cormier, S Del Signore, S Hagerty, E Stack, H Ryu, R Ferrante

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q(10) (CoQ(10)). We have reported that CoQ(10) is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ(10) slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ(10) from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ(10) significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ(10) resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ(10) and CoQ(9) were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ(10) elevated CoQ(10) plasma levels and significantly increased brain levels of CoQ(9), CoQ(10), and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ(10) exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ(10) in HD patients are warranted. # # #

Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2006 Apr 17; [Epub ahead of print]

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