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J Neurosci. August 1, 2017;

Opposing effects of valproic acid treatment mediated by histone deacetylase inhibitor activity in four transgenic X. laevis models of retinitis pigmentosa.

Vent-Schmidt RY , Wen RH , Zong Z , Chiu CN , May CG , Tam BM , Moritz OL .

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, with a phase II trial for RP underway. However, the therapeutic mechanism is unclear, with minimal research supporting its use in RP.We investigated the effects of VPA on Xenopus 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 HDAC inhibitors, but not other antipsychotics, chemical chaperones, or VPA structural analogues. In wildtype retinas, VPA treatment increased histone H3 acetylation. Additionally, electron microscopy showed increased autophagosomes in rod inner segments with HDAC inhibitor 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 HDAC inhibitor treatment is contraindicated for some RP cases. Retinitis pigmentosa (RP) is an inherited, degenerative retinal disease that leads to blindness, for which no therapy is available. We determined that valproic acid (VPA), currently undergoing a phase-II trial for RP, has both beneficial and detrimental effects in animal models of RP, depending on the underlying disease mechanism, and that both effects are due to HDAC inhibition, possibly linked to autophagy regulation. Off-label use of VPA and other HDAC inhibitors for treatment of RP should be limited to a research setting until this effect is understood and can be predicted. Our study suggests that unless genotype is accounted for, clinical trials for RP treatments may give negative results due to multiple disease mechanisms with differential responses to therapeutic interventions.

PubMed ID: 27940988
Article link: J Neurosci.

Genes referenced: rho

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