The Role of Pharmacogenetics and Advances in Gene Therapy in the Treatment of Diabetic Retinopathy

Agarwal, Aniruddha; Ingham, Sally A; Harkins, Keegan; Diana, V.; Nguyen, Quan Dong

doi:10.2217/pgs.15.173

Cited by 14 publications

(11 citation statements)

References 107 publications

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“…In case of T2D leading to DR, the implications have been insightful as the polymorphism discovery in the HLA region accounts for only 5–10% of disease heritability [126] which states a large constituent of genetic predisposition to T2D, that still requires an identification portfolio. This reflection suggests that environmental or epigenetic factors might influence the disease predisposition [18] and its inclination towards the triggered metabolic and signaling pathways.…”

Section: Genome Wide Association Studies (Gwas)mentioning

confidence: 99%

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Pradhan¹,

Upadhyay²,

Tiwari³

et al. 2016

New Front Ophthalmol

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Intensification in the frequency of diabetes and the associated vascular complications has been a root cause of blindness and visual impairment worldwide. One such vascular complication which has been the prominent cause of blindness; retinal vasculature, neuronal and glial abnormalities is diabetic retinopathy (DR), a chronic complicated outcome of Type 1 and Type 2 diabetes. It has also become clear that “genetic” variations in population alone can’t explain the development and progression of diabetes and its complications including DR. DR experiences engagement of foremost mediators of diabetes such as hyperglycemia, oxidant stress, and inflammatory factors that lead to the dysregulation of “epigenetic” mechanisms involving histone acetylation and histone and DNA methylation, chromatin remodeling and expression of a complex set of stress-regulated and disease-associated genes. In addition, both elevated glucose concentration and insulin resistance leave a robust effect on epigenetic reprogramming of the endothelial cells too, since endothelium associated with the eye aids in maintaining the vascular homeostasis. Furthermore, several studies conducted on the disease suggest that the modifications of the epigenome might be the fundamental mechanism(s) for the proposed metabolic memory’ resulting into prolonged gene expression for inflammation and cellular dysfunction even after attaining the glycemic control in diabetics. Henceforth, the present review focuses on the aspects of genetic and epigenetic alterations in genes such as vascular endothelial growth factor and aldose reductase considered being associated with DR. In addition, we discuss briefly the role of the thioredoxin-interacting protein TXNIP, which is strongly induced by high glucose and diabetes, in cellular oxidative stress and mitochondrial dysfunction potentially leading to chromatin remodeling and ocular complications of diabetes. The identification of disease-associated genes and their epigenetic regulations will lead to potential new drugs and gene therapies as well as personalized medicine to prevent or slow down the progression of DR.

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Section: Genome Wide Association Studies (Gwas)mentioning

confidence: 99%

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Pradhan¹,

Upadhyay²,

Tiwari³

et al. 2016

New Front Ophthalmol

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“…Angiogenic gene therapy shows great potential in improving ischemic cardiovascular disease 1,2 and wound healing, 3 while anti-angiogenic gene therapy is a promising approach to inhibit tumor growth 4 and ocular disease. 5 The main hurdles with this technique yet to overcome are poor gene delivery and expression efficiency at the desired site and non-specific distribution of the therapeutic genes. Due to their low immunogenicity, high efficiency in transfecting non-dividing cells, and long-term expression profile, lentiviruses may represent an effective gene delivery system for endothelial and thus angiogenic gene therapy.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

Heun

Pogoda²,

Anton

et al. 2017

Molecular Therapy

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Hypoxia promotes vascularization by stabilization and activation of the hypoxia inducible factor 1α (HIF-1α), which constitutes a target for angiogenic gene therapy. However, gene therapy is hampered by low gene delivery efficiency and non-specific side effects. Here, we developed a gene transfer technique based on magnetic targeting of magnetic nanoparticle-lentivirus (MNP-LV) complexes allowing site-directed gene delivery to individual wounds in the dorsal skin of mice. Using this technique, we were able to control HIF-1α dependent wound healing angiogenesis in vivo via site-specific modulation of the tyrosine phosphatase activity of SHP-2. We thus uncover a novel physiological role of SHP-2 in protecting HIF-1α from proteasomal degradation via a Src kinase dependent mechanism, resulting in HIF-1α DNA-binding and transcriptional activity in vitro and in vivo. Excitingly, using targeting of MNP-LV complexes, we achieved simultaneous expression of constitutively active as well as inactive SHP-2 mutant proteins in separate wounds in vivo and hereby specifically and locally controlled HIF-1α activity as well as the angiogenic wound healing response in vivo. Therefore, magnetically targeted lentiviral induced modulation of SHP-2 activity may be an attractive approach for controlling patho-physiological conditions relying on hypoxic vessel growth at specific sites.

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“…Despite the improved visual outcomes of patients with DR treated with anti-VEGF agents, the unresponsiveness to the anti-VEGFs has been reported previously. Genetic polymorphisms appear to be another variable to analyze when the anti-VEGF therapy is ineffective [42]. In addition, VEGF protein expression has been shown to be influenced by genetic variations at VEGF gene locus, and the increased transcript levels of VEGF in the vitreous fluid promoted the development and progression of DR [36].…”

Section: Discussionmentioning

confidence: 99%

Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Yang

Zhang

et al. 2020

Horm Metab Res

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The associations between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of type 2 diabetic retinopathy (DR) – proliferative diabetic retinopathy (PDR), and nonproliferative diabetic retinopathy (NPDR) – remain unclear. A systematic search and meta-analysis using odds ratio (OR) with 95% confidence interval (CI) was performed to evaluate the association. Our study concluded 26 studies containing 10 single nucleotide polymorphisms (SNPs). In Asian populations, rs3025039 polymorphism was associated with DR risk, while in overall populations and Caucasians, the DR risk was increased by association with rs2010963. There was a significant association between rs25648 and rs833061 and DR risk in Caucasians. DR risks were found to be significantly associated between rs3025021, rs13207351, and rs2146323 in either overall populations, Caucasians or Asians. Besides, in overall and Asian populations, rs699947 and rs3025039 were associated with PDR risk. rs1570360, rs3025039, and rs833061 played a key role in PDR etiology in Caucasians. rs2010963 was associated with increased risk of PDR in overall populations. A significant association between rs699947, rs3025039, and rs833061 and NPDR risk in overall populations and Asians was found. A significant association was observed between rs2010963 and increased NPDR risk in overall and Caucasian populations. This study provides a new insight into the parthenogenesis of diabetic retinopathy. Targeting VEGF SNPs may be a potential of therapeutic approach for the treatment of DR, PDR, and NPDR.

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The Role of Pharmacogenetics and Advances in Gene Therapy in the Treatment of Diabetic Retinopathy

Cited by 14 publications

References 107 publications

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis

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