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Ruanne Y J Lai, Zusheng Zong, Beatrice M Tam, Chris May, Orson L Moritz; Opposing effects of valproic acid treatment in four animal models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4370.
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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 autosomal dominant RP; in some transgenic models of RP based on rhodopsin mutations, retinal degeneration (RD) can be rescued by dark rearing, or exacerbated by light exposure. Valproic acid (VPA) is a proposed RP treatment, with two phase II clinical trials underway. However, the therapeutic mechanism of VPA for RP, if any, is unclear and no basic research supporting its use in RP has been published. Therefore, we investigated the effect of VPA on transgenic X. laevis models of RP expressing human P23H (hP23H), hT17M, hT4K, and hQ344Ter rhodopsins.
Transgenic and wildtype X. laevis tadpoles were raised in cyclic light or complete darkness and treated with varying concentrations of VPA. Treatment began on post-fertilization day 3 and continued through day 14, after which the animals were sacrificed and genotyped. From each animal, one eye was solubilized and rhodopsin content was analyzed. The contralateral eyes were fixed, cryosectioned, and imaged by confocal microscopy.
Our findings revealed that VPA dramatically rescued RD associated with hP23H rhodopsin in a dose-dependent manner. This effect was mediated by clearing of the mutant hP23H rhodopsin from rod inner segments. The magnitude of the rescue effect was equal to that of dark rearing. In the group where both VPA treatment and dark-rearing were combined, no additive effect was observed. Contrastingly, VPA dramatically exacerbated RD in hT17M rhodopsin animals. Effects in hT4K and hQ344Ter rhodopsin models were less pronounced.
VPA rescues RD caused by hP23H rhodopsin, but exacerbates RD caused by hT17M rhodopsin. VPA treatment and light restriction were not synergistic in the case of hP23H rhodopsin, while VPA exacerbation of RD caused by hT17M rhodopsin required light exposure. VPA treatment decreases the burden of misfolded hP23H rhodopsin in rod photoreceptors, possibly through activation of autophagy. Our results indicate that the success or failure of VPA treatment in RP is likely to be highly dependent on the underlying genotype, and that VPA treatment will be contraindicated for some RP cases. We are currently investigating the therapeutic potential of compounds structurally and functionally related to VPA.
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