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Ruanne Y J Lai, Zusheng Zong, Beatrice M Tam, Christopher Galen May, Orson L Moritz; Opposing effects of HDAC inhibitors in hP23H and hT17M animal models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5407.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder for which no treatment is available. Mutations in the rhodopsin gene have been linked to RP. Valproic acid (VPA) is a proposed RP treatment, with two phase II clinical trials underway. However, the mechanism of VPA for RP, if any, is unclear. Therefore, we investigated the effect of VPA on transgenic X. laevis models of RP expressing human P23H (hP23H) and hT17M rhodopsins. To elucidate origin of the effects of VPA, we tested structural and functional analogs of VPA, including mood stabilizers, molecular chaperones and HDAC inhibitors.
Transgenic and wildtype X. laevis tadpoles were raised in cyclic light or complete darkness and treated with VPA or other analogs of VPA. Treatment began on post-fertilization day 2 and continued through day 14, after which the animals were sacrificed and genotyped. One eye was solubilized and rhodopsin level was analyzed. The contralateral eye was fixed, cryosectioned, and imaged by confocal microscopy.
We found that VPA and the HDAC inhibitor, sodium butyrate (NaBu), independently rescued RD associated with hP23H rhodopsin dose-dependently. Effect of VPA was mediated by clearing of the mutant hP23H rhodopsin from rod inner segments. The magnitude of the rescue effect from both compounds was equal to that of dark-rearing, but the effect of combined drug treatment and dark-rearing was not additive. Contrastingly, VPA and NaBu dramatically exacerbated RD in hT17M rhodopsin animals in cyclic light conditions, but this detrimental effect was not observed in dark-reared animals. Effects of other structural and functional analogs of VPA were not significant.
VPA and NaBu treatments both rescue RD caused by hP23H rhodopsin, but exacerbate RD caused by hT17M rhodopsin. VPA or NaBu treatment combined with light restriction were not synergistic in hP23H animals, while VPA or NaBu exacerbation of RD caused by hT17M rhodopsin required light exposure. VPA treatment decreases the burden of misfolded hP23H rhodopsin in rod photoreceptors. Both compounds are HDAC inhibitors, and this activity appears to be responsible for both the beneficial and detrimental effects. Our results indicate that the success or failure of pharmacological therapy in RP is likely to be highly dependent on the underlying genotype, and that VPA treatment will be contraindicated for some RP cases.
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