Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells

Schmitt, H; Schlamp, Cassandra L.; Nickells, Robert W.

doi:10.1016/j.neulet.2015.12.012

Cited by 31 publications

(19 citation statements)

References 41 publications

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“…Gene therapy (Dahlmann-Noor et al, 2010; Johnson et al, 2010; Martin et al, 2003) can provide a mechanism to induce or repress any of the previously listed targets, while broader-acting interventions such as exercise can have wide-ranging effects (Roddy and Ellemberg, 2012). Histone deacetylase inhibitors, for example, are currently used for cancer treatment and are considered neuroprotective in CNS disease (Pelzel et al, 2010; Schmitt et al, 2015). Similarly, potential drugs which are already marketed for other uses include CoQ10 (which can serve as an electron carrier in the mitochondrial electron transport chain (Lee et al, 2014)), losartan (which is a selective angiotensin 1 receptor that can modulate scleral rigidity via the TGFβ pathway (Quigley et al, 2015)), and others.…”

Section: Biochemical Pathways and Potential Treatmentsmentioning

confidence: 99%

Neuroprotection for glaucoma: Requirements for clinical translation

Levin

Crowe

Quigley

et al. 2017

Experimental Eye Research

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Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular pressure. There is currently a great potential for research surrounding neuroprotection as it relates to glaucoma. Anatomical targets for neuroprotection should focus on upstream rather than downstream factors, and could include any part of the retinal ganglion cell, the glia, especially astrocytes or Muller cells, and vasculature. The great number of anatomical targets is exceeded only by the number of possible biochemical pathways and potential treatments. Successful treatment may be accomplished through the targeting of one or even a combination of multiple pathways. Once a treatment is shown effective in vitro, it should be evaluated in vivo with carefully chosen animal models and studied in sufficient numbers to detect statistically and clinically significant effects. Such a drug should have few systemic side effects and its delivery should be optimized so as to encourage compliance. There are still a multitude of possible screens available to test the efficacy of a neuroprotective drug and a single gold standard is ideal for the accurate assessment and comparison of new drugs. Future studies in neuroprotection should investigate the genetic component of the disease, novel pharmaceutical agents for new or known pathways, modulations of scleral biomechanics, and relation to research of other complex disorders of the central nervous system.

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Section: Biochemical Pathways and Potential Treatmentsmentioning

confidence: 99%

Neuroprotection for glaucoma: Requirements for clinical translation

Levin

Crowe

Quigley

et al. 2017

Experimental Eye Research

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“…For example, intracellular free Cu must be strictly limited as the uncontrolled accumulation of Cu may lead to increased oxidative stress and damage to macromolecules (7–9). Similarly, metalloproteins are essential to numerous biological processes and represent a broad class of validated clinical targets (10, 11). Metalloprotein inhibitors (MPi) are generally comprised of a metal-binding pharmacophore (MBP) and ‘backbone’ substituents (12).…”

Section: Introductionmentioning

confidence: 99%

The effect of metalloprotein inhibitors on cellular metal ion content and distribution

et al. 2017

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With metalloproteins garnering increased interest as therapeutic targets, designing target-specific metalloprotein inhibitors (MPi) is of substantial importance. However, in many respects, the development and evaluation of MPi lags behind that of conventional small molecule therapeutics. Core concerns around MPi, such as target selectivity and potential disruption of metal ion homeostasis linger. Herein, we used a suite of analytical methods, including energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma atomic emission spectroscopy (ICP-OES), and synchrotron X-ray fluorescence microscopy (SXRF) to investigate the effect of several MPi on cellular metal ion distribution and homeostasis. The results reveal that at therapeutically relevant concentrations, the tested MPi have no significant effects on cellular metal ion content or distribution. In addition, the affinity of the metal-binding pharmacophore (MBP) utilized by the MPi does not have a substantial influence on the effect of the MPi on cellular metal distribution. These studies provide an important, original data set indicating that metal ion homeostasis is not notably perturbed by MPi, which should encourage the development of and aid in designing new MPi, guide MBP selection, and clarify the effect of MPi on the ‘metallome’.

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“…In response to damage, RGCs undergo changes in chromatin structure that precipitate the condensation of euchromatin to heterochromatin, and the early and rapid silencing of normal gene expression. 3 – 6 These changes are largely controlled by an increase in histone deacetylase (HDAC) activity, including the translocation of HDAC3 from the cytoplasm to the nucleus shortly after damage. 3 It is not clear if these changes would present a hostile or repressive transcriptional environment to a newly introduced transgene.…”

mentioning

confidence: 99%

AAV2-Mediated Transduction of the Mouse Retina After Optic Nerve Injury

Nickells

Schmitt

Maes

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeGene therapy of retinal ganglion cells (RGCs) has promise as a powerful therapeutic for the rescue and regeneration of these cells after optic nerve damage. However, early after damage, RGCs undergo atrophic changes, including gene silencing. It is not known if these changes will deleteriously affect transduction and transgene expression, or if the therapeutic protein can influence reactivation of the endogenous genome.MethodsDouble-transgenic mice carrying a Rosa26-(LoxP)-tdTomato reporter, and a mutant allele for the proapoptotic Bax gene were reared. The Bax mutant blocks apoptosis, but RGCs still exhibit nuclear atrophy and gene silencing. At times ranging from 1 hour to 4 weeks after optic nerve crush (ONC), eyes received an intravitreal injection of AAV2 virus carrying the Cre recombinase. Successful transduction was monitored by expression of the tdTomato reporter. Immunostaining was used to localize tdTomato expression in select cell types.ResultsSuccessful transduction of RGCs was achieved at all time points after ONC using AAV2 expressing Cre from the phosphoglycerate kinase (Pgk) promoter, but not the CMV promoter. ONC promoted an increase in the transduction of cell types in the inner nuclear layer, including Müller cells and rod bipolar neurons. There was minimal evidence of transduction of amacrine cells and astrocytes in the inner retina or optic nerve.ConclusionsDamaged RGCs can be transduced and at least some endogenous genes can be subsequently activated. Optic nerve damage may change retinal architecture to allow greater penetration of an AAV2 virus to transduce several additional cell types in the inner nuclear layer.

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Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells

Cited by 31 publications

References 41 publications

Neuroprotection for glaucoma: Requirements for clinical translation

Neuroprotection for glaucoma: Requirements for clinical translation

The effect of metalloprotein inhibitors on cellular metal ion content and distribution

AAV2-Mediated Transduction of the Mouse Retina After Optic Nerve Injury

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