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Opposing effect of valproic acid treatment mediated by histone deacetylase inhibitor activity in four transgenic X. laevis models of retinitis pigmentosa Vent-Schmidt, Ying Ju Ruanne

Abstract

Retinitis pigmentosa (RP) is an inherited retinal degeneration (RD) that leads to blindness for which no treatment is available. RP is frequently caused by mutations in rhodopsin; in some animal models, RD is exacerbated by light. Valproic acid (VPA) is a proposed treatment for RP and other neurodegenerative disorders. A phase II clinical for RP was conducted in parallel of this thesis. However, the therapeutic mechanism is unclear, with minimal research supporting its use in RP. We investigated the effects of VPA on X. laevis models of RP expressing human P23H, T17M, T4K, and Q344ter rhodopsins, which are associated with RP in humans. VPA ameliorated RD associated with P23H rhodopsin and promoted clearing of mutant rhodopsin from photoreceptors. The effect was equal to that of dark-rearing, with no additive effect observed. Rescue of visual function was confirmed by electroretinography. Contrastingly, VPA exacerbated RD caused by T17M rhodopsin in light, but had no effect in darkness. Effects in T4K and Q344ter rhodopsin models were also negative. These effects of VPA were paralleled by treatment with three additional histone deacetylase inhibitors (HDACi’s), but not other antipsychotics, chemical chaperones, or VPA structural analogs. In wildtype retinas, VPA treatment increased histone H3 acetylation. Additionally, electron microscopy showed increased autophagosomes in rod inner segments with HDACi treatment, potentially linking the therapeutic effects in P23H rhodopsin animals and negative effects in other models with autophagy. Our results suggest that the success or failure of VPA treatment will be dependent on genotype and that HDACi treatment is contraindicated for some RP cases.

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