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Potentials of Gene Therapy for Diabetic Retinopathy: The Use of Nucleic Acid Constructs Containing a TXNIP Promoter.

ABSTRACT: Diabetic retinopathy (DR) is considered as a chronic eye disease leading to blindness. DR is associated with hyperglycemia-induced oxidative stress, chronic low-grade inflammation and premature cell death. DR affects retinal capillaries, neuroretina and the retinal pigment epithelium. Recently, the thioredoxin-interacting protein TXNIP has been shown as a pro-oxidative stress, pro-inflammatory and pro-apoptotic protein, highly induced by diabetes and high glucose in all cells examined including the retina. TXNIP's actions involve binding to and inhibition of anti-oxidant and thiol-reducing capacities of thioredoxins (Trx) causing cellular oxidative stress and apoptosis. Trx1 is found in the cytosol and nucleus while Trx2 is the mitochondrial isoform. Several studies provided evidence that knockdown of TXNIP by siRNA or chemical blockade ameliorates early abnormalities of DR including endothelial dysfunction, pericyte apoptosis, Müller cell gliosis and neurodegeneration. Therefore, TXNIP is considered a potential target for preventing or slowing down the progression of DR. We recently proposed that nucleic acid constructs containing a proximal TXNIP promoter linked to a redox gene or shRNA that reduces oxidative stress and inflammation may be used to treat DR. The TXNIP promoter is sensitive to hyperglycemia therefore can drive expression of the linked gene or shRNA under high glucose environment such as seen in diabetes while remaining unresponsive at physiological glucose levels. Such a TXNIP-promoter linked gene or shRNA construct can be delivered to the retina by using adeno-associated viral vectors including AAV2 and AAV2/8 or an appropriate carrier via the intravitreal or sub retinal delivery for long-term gene therapies in DR.

SUBMITTER: Lalit PS

PROVIDER: S-EPMC6519956 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Potentials of Gene Therapy for Diabetic Retinopathy: The Use of Nucleic Acid Constructs Containing a TXNIP Promoter.

Lalit P S PS Thangal Y Y Fayi Y Y Takhellambam S D SD

Open access journal of ophthalmology 20180321 2

Diabetic retinopathy (DR) is considered as a chronic eye disease leading to blindness. DR is associated with hyperglycemia-induced oxidative stress, chronic low-grade inflammation and premature cell death. DR affects retinal capillaries, neuroretina and the retinal pigment epithelium. Recently, the thioredoxin-interacting protein TXNIP has been shown as a pro-oxidative stress, pro-inflammatory and pro-apoptotic protein, highly induced by diabetes and high glucose in all cells examined including ...[more]

PMID: 31106306

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Project description:Background The relationship between uric acid (UA) and diabetic retinopathy (DR) remains ambiguous, and the results of current studies on the UA levels in patients with DR are conflicting. A meta-analysis was performed to provide a better understanding of the relationship between UA levels and DR. Methods PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until December 11, 2021 to identify eligible studies, that compared the UA levels of the case group (patients with DR) and control group (controls with diabetes and healthy participants). The weighted mean difference (WMD) with a 95% confidence interval (CI) was used to evaluate the difference in UA levels between the case and control groups. Results Twenty-one studies involving 4,340 patients with DR and 8,595 controls (8,029 controls with diabetes and 566 healthy participants) were included in this meta-analysis. We found that patients with DR had significantly higher UA levels than those in the controls with diabetes (WMD = 36.28; 95% CI: 15.68, 56.89; P < 0.001) and healthy participants (WMD = 70.80; 95% CI: 19.85, 121.75; P = 0.006). There was an obvious heterogeneity among the 21 studies (I2 = 97%, P < 0.001). Subgroup analyses of different phases of DR showed that UA levels were significantly increased in participants with proliferative diabetic retinopathy (PDR) (WMD = 46.57; 95% CI: 28.51, 64.63; P < 0.001) than in controls with diabetes; however, the difference is not statistically significant when comparing UA levels in patients with non-proliferative diabetic retinopathy (NPDR) and controls with diabetes (WMD = 22.50; 95% CI: −6.07, 51.08; P = 0.120). In addition, UA levels were higher in participants with a body mass index (BMI) ≥25.0 kg/m2 and over 15 years of diabetes. Univariate meta-regression analysis revealed that BMI (P = 0.007, Adj R2 = 40.12%) and fasting blood glucose (FBG) (P = 0.040, Adj R2 = 29.72%) contributed to between-study heterogeneity. Conclusions In conclusion, our study provides evidence that UA levels are higher in patients with DR than those in the controls, but this difference is not statistically significant in the early phases. UA might be a potential biomarker for identifying disease severity in patients with DR, rather than predicting the onset of DR among patients with diabetes. However, more prospective and high-quality clinical evidence is required to confirm these present findings. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=297708.

Project description:Localized aerosol delivery of gene therapies is a promising treatment of severe pulmonary diseases including lung cancer, cystic fibrosis, COPD and asthma. The administration of drugs by inhalation features multiple benefits including an enhanced patient acceptability and compliance. The application of a spray dried powder formulation has advantages over solutions due to their increased stability and shelf life. Furthermore, optimal sizes of the powder can be obtained by spray drying to allow a deep lung deposition. The present study optimized the parameters involved with spray drying polyplexes formed by polyethylenimine (PEI) and nucleic acids in inert excipients to generate a nano-embedded microparticle (NEM) powder with appropriate aerodynamic diameter. Furthermore, the effects of the excipient matrix used to generate the NEM powder on the biological activity of the nucleic acid and the ability to recover the embedded nanoparticles was investigated. The study showed that bioactivity and nucleic acid integrity was preserved after spray drying, and that polyplexes could be reconstituted from the dry powders made with trehalose but not mannitol as a stabilizer. Scanning electron microscopy (SEM) showed trehalose formulations that formed fused, lightly corrugated spherical particles in the range between 1 and 5 µm, while mannitol formulations had smooth surfaces and consisted of more defined particles. After redispersion of the microparticles in water, polyplex dispersions are obtained that are comparable to the initial formulations before spray drying. Cellular uptake and transfection studies conducted in lung adenocarcinoma cells show that redispersed trehalose particles performed similar to or better than polyplexes that were not spray dried. A method for quantifying polymer and nucleic acid loss following spray drying was developed in order to ensure that equal nucleic acid amounts were used in all in vitro experiments. The results confirm that spray dried NEM formulations containing nucleic acids can be prepared with characteristics known to be optimal for inhalation therapy.

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Potentials of Gene Therapy for Diabetic Retinopathy: The Use of Nucleic Acid Constructs Containing a TXNIP Promoter.

Publications

Potentials of Gene Therapy for Diabetic Retinopathy: The Use of Nucleic Acid Constructs Containing a TXNIP Promoter.

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