In Vivo Gene Expression Profiling of Retina Postintravitreal Injections of Dexamethasone and Triamcinolone at Clinically Relevant Time Points for Patient Care

Smit-McBride, Zeljka; Modjtahedi, Sara P.; Cessna, C. T.; Telander, David G.; Hjelmeland, Leonard M.; Morse, Lawrence S.

doi:10.1167/iovs.10-7084

Cited by 8 publications

(6 citation statements)

References 67 publications

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“…As a general observation and contrary to the data of steroid effects in the retina [ 9 ], there were far fewer genes with an altered expression at 1 month than at 1 week postinjection.…”

Section: Resultscontrasting

confidence: 88%

“…In conclusion, in our previous study [ 9 ], we have reported that intravitreal Dex and TAA resulted in gene expression changes which potentially altered the balance between neuroprotective and neurodegenerative processes in the retina. In this study, using the same mouse model, we investigated the effects of these steroids on gene expression in the RPE/choroid and found that the major influenced pathways are circadian rhythm and several neurotransmission pathways.…”

Section: Discussionmentioning

confidence: 89%

“…Clinical decision making may be greatly enhanced with a better appreciation of the differential gene expression induced by intravitreal steroids. In a previous study using a mouse model, we demonstrated that intravitreal steroids affect the expression of several genetic pathways and alter the balance between neuroprotective and neurodegenerative processes in retina [ 9 ]. In this sequel study we used the same model to examine the differential gene expression effects of intravitreal injections of Dex and TAA in RPE/choroid tissue in vivo , since they too are affected by both disease pathogenesis and intravitreal steroidal treatment at clinically relevant time points of 1 week and 1 month postinjection.…”

Section: Introductionmentioning

confidence: 99%

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Comparison ofIn VivoGene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide

Smit-McBride

Moisseiev

Modjtahedi

et al. 2016

Journal of Ophthalmology

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Purpose. To identify retinal pigment epithelium (RPE)/choroid genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. Methods. Differential gene expression of over 34,000 well-characterized mouse genes in the RPE/choroid of 6-week-old C57BL/6J mice was analyzed after intravitreal steroid injections at 1 week and 1 month postinjection, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpring GX 12.5 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. Results. Both triamcinolone and dexamethasone caused differential activation of genes involved in “Circadian Rhythm Signaling” pathway at both time points tested. Triamcinolone (TAA) uniquely induced significant changes in gene expression in “Calcium Signaling” (1 week) and “Glutamate Receptor Signaling” pathways (1 month). In contrast, dexamethasone (Dex) affected the “GABA Receptor Signaling” (1 week) and “Serotonin Receptor Signaling” (1 month) pathways. Understanding how intraocular steroids affect the gene expression of RPE/choroid is clinically relevant. Conclusions. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections, which likely has consequences in the dysregulation of RPE function and neurodegeneration of the retina.

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“…As a general observation and contrary to the data of steroid effects in the retina [ 9 ], there were far fewer genes with an altered expression at 1 month than at 1 week postinjection.…”

Section: Resultscontrasting

confidence: 88%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Comparison ofIn VivoGene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide

Smit-McBride

Moisseiev

Modjtahedi

et al. 2016

Journal of Ophthalmology

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“…Furthermore, we have demonstrated that our top candidate gene— Cacna2d1 —is critical for modulation of IOP in these strains. Although other positional candidates in our Chr 5 QTL, such as Nos3 and Sema3e (Supplementary Table 1 ), have been linked to glaucoma 39 – 41 , they do not fulfill our stringent selection criteria and therefore have been eliminated as candidate genes (Supplementary Table 2 ). Other positional candidates, such as Crygn and Klhl7 , have been associated with other ocular diseases 42 , 43 , but not glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

et al. 2017

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Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.

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“…This regulation influences the expression of vascular endothelial growth factor (VEGF), inhibits pro-inflammatory genes such as tumour necrosis factor-alpha (TNF-α) and other inflammatory chemokines, and induces the expression of anti-inflammatory factors such as pigment epithelium-derived factor (PEDF). [9][10][11] Some studies show that TA, at therapeutic concentrations, significantly inhibits the expression of TNF-α, interleukin 1-beta (IL-1β), thromboxane B2 (TxB2) and leukotriene B4 (LTB4), in a dose-dependent manner. 12 Additionally, TA seems to reduce the expression of matrix metalloproteinases (MMPs) and to downregulate intercellular adhesion molecule 1 (ICAM-1) on choroidal endothelial cells.…”

mentioning

confidence: 99%

Triamcinolone Acetonide for the Treatment of Diabetic Macular Oedema

Sarao¹,

Veritti²,

Lanzetta³

2012

European Ophthalmic Review

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Diabetic macular oedema is a major cause of severe visual loss whose pathogenesis appears to be complex and multifactorial. For many years laser photocoagulation has been the standard of care for the treatment of this condition. Emerging pharmacologic approaches are being evaluated through randomised controlled trials. Triamcinolone acetonide has been proposed as a promising option, due to its well-known anti-inflammatory, anti-permeability and anti-angiogenic properties. Intravitreal delivery allows bypassing of the bloodretinal barrier to achieve a more concentrated dose of steroid in the vitreal cavity for a prolonged time. Intravitreal triamcinolone acetonide is effective in reducing central macular thickness and improving visual acuity, even if the duration of action is often provisional and requires repeated injections. Drug-related and injection-related side effects have been reported; the most common are induced cataract and increased intraocular pressure. To extend the duration of steroid effects and to minimise the risk of complications, alternative routes of administration and extend-release implants are being investigated.

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In Vivo Gene Expression Profiling of Retina Postintravitreal Injections of Dexamethasone and Triamcinolone at Clinically Relevant Time Points for Patient Care

Cited by 8 publications

References 67 publications

Comparison ofIn VivoGene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide

Comparison ofIn VivoGene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Triamcinolone Acetonide for the Treatment of Diabetic Macular Oedema

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