Re:Conclusions of Clemson et al. concerning Valproic Acid are premature

Shalesh Kaushal, ,

Other Contributors:

September 20, 2010

Dear Editor,

We appreciate the interest of Van Schooneveld et al.1 in our recent BJO article.2 Our small, retrospective chart review of RP patients treated off-label with valproic acid is only the first step in the process of understanding the potential utility of the drug for patients with this sight-threatening condition, for which there are no current therapeutic options.

The size and the scope of our article was limited by the nature of a retrospective chart review, which only allows analysis of follow-up that occurred within the defined time frame. Additional factors limiting the scope and length of the study included (1) the logistical and financial complexity involved in following up patients in two geographically separated states; (2) the differences in available equipment in the two institutions; and (3) the importance of sharing a potential new treatment with the ophthalmic community sooner rather than later.

The retrospective chart review process was begun while the senior author was at the University of Florida, and because he moved from Florida to Massachusetts, the analysis was carried out in Massachusetts and appropriate Institutional Review Board approval from the Massachusetts site was published in the article.

The valproic acid treatment regimen analyzed retrospectively in the charts of the seven patients is detailed in the article. Prospective follow-up was not done, nor is it allowed under the mandate of a retrospective chart review. To clarify, the treatment of patients with valproic acid has not been stopped for any of the patients who tolerated it well (most of the patients). Our retrospective chart review reported on in the BJO article captured a relatively short period for a slowly progressive condition like RP, and we recognize that the most rigorous validation of a therapy will be a well-designed clinical trial. A prospective, multicenter, randomized, placebo-controlled clinical trial is in the final stages of preparation3 in the U.S., and we will be registering this clinical trial very soon at the U.S. clinical trials website, www.clinicaltrials.gov.

On a separate note, as part of our current clinical practice in Massachusetts, several RP patients new to our practice have been treated with valproic acid; our clinical impressions of these new patients are similar to what was reported in our article.

There is mounting evidence that valproic acid may have potent neuroprotective properties and have other beneficial effects,4-6 and we have intensive in vitro and in vivo experiments (including mice models of RP) underway. The results of our experiments in the context of retinal degenerative conditions have been reported at recent meetings.7-11 We are planning to submit these data as articles to peer-reviewed journals.

Our work has been motivated by the spirit of translational research, with the goal of more quickly identifying a promising therapeutic approach and stimulating scientific interest and further research, based on preclinical data and unexpectedly positive vision function observed in a clinical setting. Repurposing drugs such as valproic acid, which have been shown to be safe, is an economical and time-efficient way to bring new treatments to patients.

Sincerely C. Clemson R. Tzekov M. Krebs J. Checchi S. Kaushal

References:

1. Van Schooneveld MJ, Van den Born LI, Van Genderen M, Bollemeijer J -G. Conclusions of Clemson et al. concerning Valproic Acid are premature (letter). British Journal of Ophthalmology 25 August 2010.

2. Clemson CM, Tzekov R., Krebs M., Checchi JM, Bigelow C, Kaushal, S. Therapeutic potential of valproic acid for retinitis pigmentosa. British Journal of Ophthalmology. July 20, 2010 [epub ahead of print - doi: 10.1136/bjo.2009.175356]

3. See web page at: http://www.umassmed.edu/VALPROIC_ACID_SHOWN_TO_HALT_VISION_LOSS_IN_PATIENTS.aspx

4. Monti B, Polazzi E, Contestabile A. Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol. 2009 Jan;2(1):95-109.

5. Suuronen T, Nuutinen T, Ryhanen T, et al. Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells. Biochem Biophys ResCommun 2007;357:397-401.

6. Yasuda S, Liang MH, Marinova Z, et al. The mood stabilizers lithium and valproateselectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 2009;14:51-59.

7. S Kaushal, SM Noorwez, R Tzekov, D Huang, Y Li, RWen. The Effect of Valproic Acid in Mouse Models of RP. Invest. Ophthalmol. Vis. Sci. 2010 51: E-Abstract 3735.

8. SM Noorwez, S Kaushal. Dose-Dependent Differential Effect of HDAC Inhibitors on Yields of Folded P23H and WT Rhodopsin. Invest. Ophthalmol. Vis. Sci. 2010 51: E-Abstract 5979.

9. SJ Upadhyay, JA Hossain, MP Krebs, P Baciu, S Kaushal. Effect of HDAC Inhibitors on Oxidative Apoptosis of RPE Cells. Invest. Ophthalmol. Vis. Sci. 2010 51: E-Abstract 496.

10. GB Peters, III, T Banzon, A Maminishkis, SS Miller, and S Kaushal. Valproic Acid Decreases Retinal Thickness in AMD Patients and Increases Fluid Absorption Across Human Retinal Pigment Epithelium in vitro. Invest. Ophthalmol. Vis. Sci. 2010 51: E-Abstract 4957.

11. S Noorwez, S Kaushal. Dose-Dependent Differential Effect of HDAC Inhibitors on Yields of Folded Rhodopsin. XIX Biennial meeting of the International Society of Eye Research (ISER), Montreal, Canada. Abstract 797.

Conflict of Interest:

None declared

Conflict of Interest

None declared