Therapeutic potential of valproic acid for retinitis pigmentosa

C M Clemson; R Tzekov; M Krebs; J M Checchi; C Bigelow; S Kaushal

doi:10.1136/bjo.2009.175356

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Therapeutic potential of valproic acid for retinitis pigmentosa

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Author Response Re: "Need to further investigate the efficacy of valproic acid therapy in retinal degenerative disorders" letter
Radouil Tzekov
Published on: 22 March 2016
Need to further investigate the efficacy of valproic acid therapy in retinal degenerative disorders
Sujoy Khan
Published on: 22 March 2016

Published on: 22 March 2016
Author Response Re: "Need to further investigate the efficacy of valproic acid therapy in retinal degenerative disorders" letter
- Radouil Tzekov
- Other Contributors:
  , Christine Clemson, Mark Krebs, Jenna Checchi, Shalesh Kaushal
Dear Editor,
We appreciate the interest of Dr. Kahn and Dr. Philip [1] in our paper describing pilot results from a retrospective study in patients with retinitis pigmentosa (RP) treated with valproic acid (VPA) [2], and we would like to comment on the points raised by them.
Length of treatment. As mentioned in our recent reply to another letter regarding the same article [3], the length of treatment...
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Dear Editor,
We appreciate the interest of Dr. Kahn and Dr. Philip [1] in our paper describing pilot results from a retrospective study in patients with retinitis pigmentosa (RP) treated with valproic acid (VPA) [2], and we would like to comment on the points raised by them.
Length of treatment. As mentioned in our recent reply to another letter regarding the same article [3], the length of treatment reported in our study was dictated by the logistical circumstances, not by any limitations imposed by any institutional review board. Attempts to limit the duration of treatment would be unfounded, as VPA has an excellent, long-standing safety record [4, 5].
Status of the retina. There is tremendous genotypic and phenotypic heterogeneity in RP, and fundus appearance can be quite variable--from almost normal retina to very significant changes such as retinal arteriolar narrowing, optic nerve head pallor, progressive chorioretinal atrophy and highly variable geographic involvement [6]. Therefore, we felt that photographic evidence of the degree to which the retina was affected by RP would not be particularly helpful. Indeed, the design of new clinical trials for RP do not include changes in fundus characteristics. In contrast to visual field and visual acuity, electroretinographic records were not available for all the patients in the study at the time of article development. Where available, electroretinographic records were profoundly reduced and consistent with the diagnosis of retinitis pigmentosa.
Age-matched controls. As stated previously [4], we agree that a case- control study would have been a better design. This problem will be resolved with the randomized clinical trial, in which the treatment group and the control group are age-matched [7].
Conversion of Snellen BCVA to logMAR, and reporting improvement in visual acuity and visual field. We agree that the Snellen chart has numerous disadvantages and we support the notion that the ETDRS chart should be the preferred method for clinical research. At the same time, it is a fact of life that the Snellen chart remains a very popular choice (and probably number one choice) by ophthalmologists in most countries of the world and has been for more than 140 years. Conversion of Snellen best -corrected visual acuity to logMAR is an accepted and widely used method [8]. Furthermore, a method to convert Snellen acuity to approximate ETDRS letter scores was also recently developed and considered appropriate [9]. Therefore, reporting change in mean visual acuity, although limited by the small sample size of this study as stated in the article [2], is appropriate. Reporting an improvement in mean visual field area was discussed in our previous reply [4] and we consider its use appropriate, although limited by sample size.
Visual field learning effect. We agree that visual field learning effect should be accounted for in a rigorous clinical research study, and this is exactly how the subsequent clinical trial is designed. In contrast, our study, as pointed out in our previous communications [3,4], was a pilot, retrospective chart review based on clinical impressions, and there was no initial intent for this to be designed as a prospective study. As we emphasized in the article, we feel that VPA is exerting some biological effect on the retina of patients with RP. There are other anecdotal, unpublished (at this time) observations by others that appear to be consistent with ours.
Mode of action of VPA. Although we find the cited article by Osakada et al. [10] very interesting and important in supporting the role of VPA as a potential treatment in retinitis pigmentosa, the information provided in it is insufficient to support a claim for "neuroprotection and neuroregeneration in a histone-acetylation- independent manner". The part of the study by Osakada et al. using VPA was conducted in a retina explant culture setting and limited to demonstrating that VPA promoted the differentiation of proliferating cells stimulated by Wnt3a into rhodopsin- positive photoreceptor cells. Valproic acid can act through multiple mechanisms in terms of neuroprotection (11), and it is presently uncertain which of these mechanisms is the leading one when the substance is applied in the diseased retina. Significant effort is underway in our (12) and other laboratories (13, 14) to elucidate the mechanisms by which VPA is exerting neuroprotective action in in vitro and in vivo models of retinal degenerations. We will be publishing those findings in the future.
In summary, we agree with the title of the letter by Drs. Khan and Philip and concur with their statement that "VPA and related HDAC inhibitors could potentially be valuable drugs for patients with retinal degenerative disorders".
Respectfully, Radouil Tzekov, Christine Clemson, Mark Krebs, Jenna Checchi, Shalesh Kaushal
References
1. Khan S., Philip S. Need to further investigate the efficacy of valproic acid therapy in retinal degenerative disorders (letter). Br J Ophthalmol 7 February 2011.
2. Clemson CM, Tzekov R, Krebs M, Checchi JM, Bigelow C, Kaushal S. Therapeutic potential of valproic acid for retinitis pigmentosa. Br J Ophthalmol 2011; 95:89-93.
3. Clemson CM, Tzekov R, Krebs M, Checchi JM, Kaushal S. Re: Conclusions of Clemson et al. concerning valproic acid are premature. Br J Ophthalmol 2011; 95:153-154.
4. Tzekov R, Bigelow C, Clemson C, Krebs M, Checchi JM, Kaushal S. Re: Lack of scientific rationale for use of valproic acid for retinitis pigmentosa Br J Ophthalmol Online First: 22 December 2010.
5. Peterson, GM, Naunton, M. Valproate: a simple chemical with so much to offer. Journal of Clinical Pharmacy and Therapeutics 2005;30:417- 421.
6. Carr, RE, Noble KG. Retinitis pigmentosa and allied diseases. In: Guyer DR, Yannuzzi LA, Chang S, et al., eds. Retina-Vitreous-Macula 1st ed. Vol. 2. Philadelphia: W.B. Saunders, 1999:891-922.
7. ClinicalTrials web site. Trial entry: NCT01233609. http://clinicaltrials.gov/ct2/results?term=NCT01233609
8. Holladay JT. Proper method for calculating average visual acuity. J Refract Surg. 1997 Jul-Aug;13(4):388-91.
9. Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing Snellen visual acuity measurements. Retina. 2010 Jul-Aug;30(7):1046-50.
10. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signalling promotes regeneration in the retina of adult mammals. J Neurosci. 2007;27:4210-9.
11. Monti B, Polazzi E, Contestabile A. Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol. 2009 Jan;2(1):95-109.
12. Noorwez SM, Kaushal S. Dose-Dependent Differential Effect of HDAC Inhibitors on Yields of Folded P23H and WT Rhodopsin. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 5979.
13. Alsarraf O, Mani SK, Menick DR, Crosson CE. Reduced Histone Deacetylase Activity Protects the Retina From Ischemic Injury. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 4714.
14. L. Yang. Valproic Acid Prevents Photoreceptor Cell Apoptosis in Retinitis Pigmentosa Mice by Increasing Bcl-2 Expression. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 3691.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 22 March 2016
Need to further investigate the efficacy of valproic acid therapy in retinal degenerative disorders
- Sujoy Khan, Consultant Immunologist, Frimley Park Hospital NHS Foundation Trust, Frimley, Surrey, GU16 7UJ, UK
- Other Contributors:
  Swetha Philip, Consultant Ophthalmologist, Christian Medical College & Hospital, Vellore, India
Dear Editor,
We have a few concerns on the report by Clemson CM et al on the efficacy of valproic acid (VPA) in 7 patients with retinitis pigmentosa (RP) [1]. Was the time period of 6 months for using VPA the maximum time that was allowed by the institutional review boards? The degree to which the retina was affected by RP was not mentioned in each case (either in the form of photographic evidence or by electro...
Show More

Dear Editor,
We have a few concerns on the report by Clemson CM et al on the efficacy of valproic acid (VPA) in 7 patients with retinitis pigmentosa (RP) [1]. Was the time period of 6 months for using VPA the maximum time that was allowed by the institutional review boards? The degree to which the retina was affected by RP was not mentioned in each case (either in the form of photographic evidence or by electrophysiological studies). Age -matched appropriate controls need to be incorporated in future studies as younger retinas or retinas lesser affected by RP usually respond better to treatment [2]. Conversion of vision from Snellens acuity chart into logMAR has a risk of wrongly estimating visual acuity given the inherent pitfalls of the Snellens acuity test [3]. Therefore to extrapolate and show improvement in the mean of visual field and visual acuity is inappropriate. The authors did not report the number of visual field plots that were done pre-treatment (except patient 5), as an improvement in visual field in patients could be an improvement in the learning curve and not a real improvement in visual field.
Although this paper calls for a well-designed prospective case- control study, it does provide proof-of-concept that valproic acid may have retinal neuroprotective effects as observed in animal models [4, 5]. VPA offers neuroprotection and neuroregeneration in a histone-acetylation- independent manner, more likely involving the Wnt (wingless-type MMTV integration site family)/beta-catenin signalling pathway [5]. Sustained Wnt2b expression helped maintain undifferentiated retinal stem cells in the ciliary marginal zone, promoted proliferation of retinal stem cells in vitro, including regeneration of rhodopsin-positive photoreceptor cells in the RP mouse model. VPA and related HDAC inhibitors could potentially be valuable drugs for patients with retinal degenerative disorders and should not be discounted without good evidence to the contrary.
References:
1. Clemson CM, Tzekov R, Krebs M, Checchi JM, Bigelow C, Kaushal S. Therapeutic potential of valproic acid for retinitis pigmentosa. Br J Ophthalmol. 2011;95:89-93.
2. Eballe AO, Koki G, Emche CB, Bella LA, Kouam JM, Melong J. Blindness and visual impairment in retinitis pigmentosa: a Cameroonian hospital-based study. Clin Ophthalmol. 2010;4:661-5.
3. McGraw P, Winn B, Whitaker D. Reliability of the Snellen chart. BMJ 1995;310:1481-2.
4. Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S, Lagr?ze WA. Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Invest Ophthalmol Vis Sci. 2010;51:526-34.
5. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signalling promotes regeneration in the retina of adult mammals. J Neurosci. 2007;27:4210-9.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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