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

Vent-Schmidt, Ruanne Y.J.; Wen, Runxia; Zong, Zusheng; Chiu, Colette N.; Tam, Beatrice M.; May, Christopher G.; Moritz, Orson L.

doi:10.1523/jneurosci.1647-16.2016

Cited by 31 publications

(27 citation statements)

References 78 publications

(34 reference statements)

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“…One possible explanation is that rd1 and rd10 models have differential responses to DHA. This has been reported for the histone-deacetylase inhibitor valproic acid, which shows opposing effects in rd1 (neuroprotective) rd10 (deleterious) mice (Mitton et al, 2014) and across four different frog models of RP (Vent-Schmidt et al, 2017). In addition valproic acid has produced inconsistent results in clinical trials with RP patients (Chen et al, 2019;Todd and Zelinka, 2017;Totan et al, 2017).…”

Section: Discussionmentioning

confidence: 92%

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Zhang

Chen

et al. 2020

Preprint

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Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly humanapproved drugs, were tested across six concentrations. Statistically, 113 compounds achieved "hit" status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of crossspecies phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.

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Section: Discussionmentioning

confidence: 92%

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Zhang

Chen

et al. 2020

Preprint

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“…15 Collectively, these findings support a hypothesis that VPA could exert efficacy in ADRP mutations that result in protein misfolding and aberrant subcellular localization, 16,17 Indeed, recently, VPA was shown to have ameliorative effects in a Xenopus model of the prolineto-histidine mutation at codon 23 RHO mutation but exerted apparently negative effects in other mutations. 18 In a small uncontrolled study, 7 patients with RP (all genetic types) received 2 to 6 months of 500 mg to 750 mg VPA daily, 19,20 and 9 of 13 eyes showed improvement in visual field, while 4 showed stable or decreased field sensitivity. The effect size was modest (approximately >10%) and, when compared with expected visual field decline, statistically significant (P < .02).…”

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confidence: 99%

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa

et al. 2018

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IMPORTANCE There are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness. OBJECTIVES To evaluate the potential efficacy and assess the safety of orally administered valproic acid (VPA) in the treatment of autosomal dominant retinitis pigmentosa. DESIGN, SETTING, AND PARTICIPANTS Multicenter, phase 2, prospective, interventional, placebo-controlled, double-masked randomized clinical trial. The study took place in 6 US academic retinal degeneration centers. Individuals with genetically characterized autosomal dominant retinitis pigmentosa were randomly assigned to receive treatment or placebo for 12 months. Analyses were intention-to-treat. INTERVENTIONS Oral VPA 500 mg to 1000 mg daily for 12 months or placebo. MAIN OUTCOMES AND MEASURES The primary outcome measure was determined prior to study initiation as the change in visual field area (assessed by the III4e isopter, semiautomated kinetic perimetry) between baseline and month 12. RESULTS The mean (SD) age of the 90 participants was 50.4 (11.6) years. Forty-four (48.9%) were women, 87 (96.7%) were white, and 79 (87.8%) were non-Hispanic. Seventy-nine participants (87.8%) completed the study (42 [95.5%] received placebo and 37 [80.4%] received VPA). Forty-two (46.7%) had a rhodopsin mutation. Most adverse events were mild, although 7 serious adverse events unrelated to VPA were reported. The difference between the VPA and placebo arms for mean change in the primary outcome was −150.43 degree 2 (95% CI, −290.5 to −10.03; P = .035). CONCLUSIONS AND RELEVANCE This negative value indicates that the VPA arm had worse outcomes than the placebo group. This study brings to light the key methodological considerations that should be applied to the rigorous evaluation of treatments for these conditions. This study does not provide support for the use of VPA in the treatment of autosomal dominant retinitis pigmentosa.

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“…Dark-reared tadpoles (age 10 weeks, stage 56; offspring of a heterozygous transgenic and WT animal) or siblings exposed to cyclic light for 1 week, were anesthetized in 0.01% Tricaine in 0.1X MMR. ERG recordings to a series of 448-nm blue light flashes of increasing intensity from a light-emitting diode source were obtained as described by Vent-Schmidt et al 35 The recording equipment incorporated a 1-Hz low-frequency cutoff filter and a 300-Hz high-frequency cut-off filter. Following ERG analysis tadpoles were genotyped to distinguish bP23H and WT animals as previously described.…”

Section: Erg Recordingsmentioning

confidence: 99%

“…Following ERG analysis tadpoles were genotyped to distinguish bP23H and WT animals as previously described. 35…”

Section: Erg Recordingsmentioning

confidence: 99%

Electrophysiological Changes During Early Steps of Retinitis Pigmentosa

Bocchero

Tam

Chiu

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The rhodopsin mutation P23H is responsible for a significant portion of autosomaldominant retinitis pigmentosa, a disorder characterized by rod photoreceptor death. The mechanisms of toxicity remain unclear; previous studies implicate destabilization of P23H rhodopsin during light exposure, causing decreased endoplasmic reticulum (ER) exit and ER stress responses. Here, we probed phototransduction in Xenopus laevis rods expressing bovine P23H rhodopsin, in which retinal degeneration is inducible by light exposure, in order to examine early physiological changes that occur during retinal degeneration. METHODS. We recorded single-cell and whole-retina responses to light stimuli using electrophysiology. Moreover, we monitored morphologic changes in rods after different periods of light exposure. RESULTS. Initially, P23H rods had almost normal photoresponses, but following a brief light exposure varying from 4 to 32 photoisomerizations per disc, photoresponses became irreversibly prolonged. In intact retinas, rods began to shed OS fragments after a rodsaturating exposure of 12 minutes, corresponding to approximately 10 to 100 times more photoisomerizations. CONCLUSIONS. Our results indicate that in P23H rods light-induced degeneration occurs in at least two stages, the first involving impairment of phototransduction and the second involving initiation of morphologic changes.

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Opposing Effects of Valproic Acid Treatment Mediated by Histone Deacetylase Inhibitor Activity in Four TransgenicX. laevisModels of Retinitis Pigmentosa

Cited by 31 publications

References 78 publications

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa

Electrophysiological Changes During Early Steps of Retinitis Pigmentosa

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