June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Unpredictable Consequences of Systemic Valproic Acid Treatment on the Rate of Photoreceptor Loss in Different Pde6b Rd-mutations
Author Affiliations & Notes
  • Kenneth Mitton
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
    Pediatric Retinal Research Laboratory, Eye Research Institute of Oakland University, Rochester, MI
  • David Byrd
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
  • Eduardo Guzman
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
    Pediatric Retinal Research Laboratory, Eye Research Institute of Oakland University, Rochester, MI
  • Adrianne Wallace
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
    Pediatric Retinal Research Laboratory, Eye Research Institute of Oakland University, Rochester, MI
  • Trung Tran
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
  • Jason Sotzen
    Control of Gene Expression Lab, Eye Research Institute of Oakland University, Rochester, MI
  • Footnotes
    Commercial Relationships Kenneth Mitton, None; David Byrd, None; Eduardo Guzman, None; Adrianne Wallace, None; Trung Tran, None; Jason Sotzen, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1593. doi:
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      Kenneth Mitton, David Byrd, Eduardo Guzman, Adrianne Wallace, Trung Tran, Jason Sotzen; Unpredictable Consequences of Systemic Valproic Acid Treatment on the Rate of Photoreceptor Loss in Different Pde6b Rd-mutations. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1593.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: VPA is an FDA approved anticonvulsant whose activity as a histone deacetylase inhibitor was discovered only recently, generating intense interest for its potential use in epigenetic therapy. Clinical trials are recruiting patients to evaluate VPA’s therapeutic potential for AD-RP. Given that VPA’s effects on gene expression are non-specific, could VPA reduce or accelerate photoreceptor loss in RP-patients harboring different mutations? We compared systemic VPA treatment on retinal neurotrophic gene expression and photoreceptor loss in rd-mice with different mutations of Pde6b.

Methods: Expression of Bdnf, Gdnf, Cntf, and Fgf2 were measured by real-time PCR after single and multiple VPA doses in wild-type and Pde6brd1/rd1 mice. Pde6brd10/rd10 mice were also treated to evaluate a partial loss-of-function model. Retinal morphology was assessed with virtual microscopy.

Results: In post-natal mice, a single systemic dose of VPA caused substantial increases in the expression of Bdnf (3x) and Gdnf (10x) in the neural retina within 18 hours. Cntf and Fgf2 expression decreased 70%. These large gene expression changes did not persist after multiple days of dosing. Daily injections with VPA (P9-P19) reduced photoreceptor loss in Pde6brd1/rd1 mice. By P20, VPA treated mice had several rows of rod nuclei, compared to a single row remaining in PBS injected littermates. Starting treatment later, or dosing every second day, also rescued photoreceptors. VPA treatment did not reduce rod loss in Pde6brd10/rd10 mice. Some PBS-treated Pde6brd10/rd10 littermates may have had slightly more rod-nuclei than their VPA treated counterparts, although this difference was not statistically significant with the numbers tested. VPA disrupted the lens bow region morphology in some mice.

Conclusions: A single systemic dose of VPA caused increases and decreases the retinal expression of different neurotrophic factor genes. While systemic VPA treatment slowed the rate of photoreceptor loss in Pde6brd1/rd1 mice, it did not benefit degenerating photoreceptors in Pde6brd10/rd10 mice. We conclude that systemic VPA was not universally beneficial for degenerations involving different functional mutations of the same gene. These results suggest that human clinical trials with VPA should best be limited to AD-RP patients with identified molecular mutations.

Keywords: 615 neuroprotection • 494 degenerations/dystrophies • 648 photoreceptors  
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