Opposing Effects of Valproic Acid Treatment Mediated by Histone Deacetylase Inhibitor Activity in Four Transgenic X. laevis Models of Retinitis Pigmentosa

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, 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.

Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP

“…Likewise, VPA had opposing effects on the degeneration of rod photoreceptors in two Pde6b mutation models, the rd1 and the rd10 mouse, in which rd1 photoreceptors were protected by VPA treatment, whereas it, in contrast, accelerated the rd10 photoreceptor degeneration (Mitton et al, 2014). Similar discrepancies have been seen in other studies (Berner and Kleinman, 2016), and the use of VPA in people with RP has not resulted in a consensus on whether or not this is a valuable treatment option, or if it may actually be negative (Dias et al, 2018;Vent-Schmidt et al, 2017). The situation with HDAC involvement in RD, which as discussed above are indeed heterogenous, is thus extremely complex.…”

“…TSA was similarly able to reduce cone cell death in the cone degeneration model cpfl1 in explant culturing, and, more importantly, in vivo through intravitreal injection (Trifunovic et al, 2016). On the other hand, yet another broad HDAC inhibitor, valproic acid (VPA), exhibited either protective or detrimental effects in Xenopus laevis models of rhodopsin mutation-based RP, depending on the exact type of genetic defect (Vent-Schmidt et al, 2017). Likewise, VPA had opposing effects on the degeneration of rod photoreceptors in two Pde6b mutation models, the rd1 and the rd10 mouse, in which rd1 photoreceptors were protected by VPA treatment, whereas it, in contrast, accelerated the rd10 photoreceptor degeneration (Mitton et al, 2014).…”

Inhibition of Epigenetic Modifiers LSD1 and HDAC1 Blocks Rod Photoreceptor Death in Mouse Models of Retinitis Pigmentosa

“…A number of previous studies have tested epigenetic modifiers as possible therapeutics for retinitis pigmentosa. Some of these have focused on the neuroprotective effects of blocking HDAC activity by such nonselective inhibitors as TSA, valproic acid (VPA), and sodium butyrate (Chuang et al, 2009;, all of which have some protective effect on RP (Mitton et al, 2014;Zhang et al, 2015;Berner and Kleinman, 2016;Todd and Zelinka, 2017;Vent-Schmidt et al, 2017). The broad-spectrum HDAC inhibitor VPA has been tested as a therapeutic agent for retinal degeneration with mixed results (Clemson et al, 2011;Kumar et al, 2014;Iraha et al, 2016;Totan et al, 2017).…”

Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases

“…151 Moreover, VPA was demonstrated to have a beneficial effect in an in vitro model characterized by P23H mutation of rhodopsin, while it had a detrimental effect on the degeneration of the retina in the T17 M model of RP, this latter effect seemingly due to inhibition of HDAC. 152 The role of HDAC6 in retinal degeneration was specifically investigated by Leyk et al, 153 who demonstrated that mousederived cone-like 661W cells do express HDAC6 and that the enzyme is active in that model because treatment with specific inhibitors led to α-tubulin hyperacetylation. Inhibition of HDAC6 protected the cells from oxidative stress induced by H 2 O 2 .…”