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 under way. 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. In contrast, 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 (
HDAC) inhibitors, but not other
antipsychotics, chemical chaperones, or VPA structural analogues. In WT retinas, VPA treatment increased
histone H3 acetylation. In addition, electron microscopy showed increased autophagosomes in rod inner segments with
HDAC inhibitor (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 is dependent on genotype and that HDACi treatment is contraindicated for some RP cases.SIGNIFICANCE STATEMENT
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
histone deacetylase (HDAC) inhibition possibly linked to autophagy regulation.
Off-label use of VPA and other
HDAC inhibitors for the treatment of RP should be limited to the 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.