Is Asthma Related to Choroidal Neovascularization?

Sun, Yaoyao; Yu, Wenzhen; Huang, Lvzhen; Hou, Jing; Gong, Peihua; Zheng, Yi; Zhao, Mingwei; Zhou, Peng; Li, Xiaoxin

doi:10.1371/journal.pone.0035415

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…We consider that this discrepancy could result from sample size of ethnic group. Other that, the associations between hypertension, CAD, DM, asthma and PCV have been inconsistent [20,21]. Interestingly, PCV is featured by the formation of a branching vascular network (BVN) and polypoidal dilated lesions at vessel termini [22].…”

Section: Discussionmentioning

confidence: 99%

Associations of systemic, serum lipid and lipoprotein metabolic pathway gene variations with polypoidal choroidal vasculopathy in China

Zhao

et al. 2019

PLoS ONE

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BackgroundTo investigate the association of systemic, serum lipids and genetic variants in the high-density lipoprotein (HDL) metabolic pathway with polypoidal choroidal vasculopathy (PCV) in China.MethodsThe case-control study was included 150 controls and 66 cases with PCV. Serum levels of total cholesterol (TC), low-density lipoprotein (LDL), HDL, triglycerides (TG), apolipoprotein A1 (APOA1), apolipoprotein B (APOB) together with systemic risk factors including gender, hyperlipidemia, diabetes mellitus (DM), hypertension, coronary artery disease (CAD) and asthma were identified. All subjects were genotyped for four single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway: rs10468017 of hepatic lipase (LIPC), rs12678919 of lipoprotein lipase (LPL), rs3764261 and rs173539 of cholesterol ester transfer protein (CETP) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Student’s t-tests, chi-square tests, anova and logistic regression were used to evaluate associations.ResultsHyperlipidemia was a risk factor (odds ratio (OR) = 1.19, P = 0.001) for PCV. HDL, LDL and APOB levels were associated with PCV (OR = 0.001, P = 0.004; OR = 0.099, P = 0.010; OR = 0.839, P = 0.018). Higher level of TC was potently associated with increased risk of PCV (OR = 109.8, P = 0.000). LIPC rs10468017 was a risk factor for PCV (OR = 11.68, P = 0.000). CETP rs3764261 conferred a decreased risk for PCV (OR = 0.08, P = 0.000). No associations of LPL rs12678919 or CETP rs173539 with PCV were found. Mean level of HDL increased with T allele of the CETP gene (p = 0.026): 1.24 mmol/L (±0.31) for the GG genotype and 1.66 mmol/L (±0.54) for the TT genotype. Additionally, T allele was associated with the following increase in APOA1: 136.78 mg/dl (±20.53) for the CC genotype and 149.57 mg/dl (±22.67) for the TT genotype of LIPC and 137.91 mg/dl (±20.36) for the GG genotype and 162.67 mg/dl (±22.50) for the TT genotype of CETP gene.ConclusionOur study suggested that the significant association was found between hyperlipidemia, the serum levels of TC, HDL, LDL and APOB and PCV. The result of present study also showed that the association of LIPC rs10468017 and CETP rs3764261 with PCV.

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Section: Discussionmentioning

confidence: 99%

Associations of systemic, serum lipid and lipoprotein metabolic pathway gene variations with polypoidal choroidal vasculopathy in China

Zhao

et al. 2019

PLoS ONE

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“… 27 In the mouse model of CNV, anti-complement therapeutics targeting different steps in the cascade have been found to be efficacious in reducing CNV, concomitant with a reduction in Vegfa. These complement inhibitors include small interfering RNA (siRNA) against CFB, 30 the C3 convertase inhibitor compstatin, 31 antibodies against the anaphylatoxins C3a and C5a, 32 and membrane-targeted or non-membrane-targeted soluble CD59. 33 , 34 Likewise, CR2-fH has been shown to reverse morphological changes in RPE and Bruch’s membrane in mouse seen after continuous smoke exposure.…”

Section: Discussionmentioning

confidence: 99%

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Schnabolk

Parsons

Obert

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice. Secretion of CR2-fH was confirmed in polarized retinal pigment epithelium (RPE) cells. A safe concentration of AAV5-VMD2-CR2-fH was identified using electroretinography, optical coherence tomography (OCT), RPE morphology, and antibody profiling. One month after gene delivery, CNV was induced using argon laser photocoagulation. OCT assessment demonstrated reduced CNV with AAV5-VMD2-CR2-fH administration. Bioavailability studies revealed that gene-therapy delivered similar levels of CR2-fH to the RPE/choroid as treatment by intravenous injections, and C3a ELISA verified reduced CNV-associated ocular C3a production. These results contribute to existing data illustrating the importance of the AP of complement in CNV development and its potential role in AMD treatment. Demonstration of AAV-vector efficacy opens new avenues for the development of treatment strategies.

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“…On the other hand, the highly comparable binding of compstatin to human and NHP C3 was recently confirmed by surface plasmon resonance (SPR)-based studies, in which the binding profiles of Cp40 and related analogs were almost identical for C3 from humans, baboons, and cynomolgus and rhesus monkeys [29]. In view of this consistently observed primate specificity of compstatin analogs, recent studies reporting the effects of compstatin-mediated C3 inhibition in rodent models of disease [30,31] and using a commercial, non-licensed compstatin product (sold by Tocris) can only be explained as experimental artifacts. Moreover, the product tested in these studies corresponds to the original compstatin, which is up to 6,000-fold less active than the derivatives currently in clinical development.…”

Section: Molecular Development Of Compstatinmentioning

confidence: 93%

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

Mastellos

Yancopoulou²,

Kokkinos³

et al. 2015

Eur J Clin Investigation

189

231

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There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational “wet” and in silico synthetic approaches and an array of biophysical, structural, and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogs that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception.

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Is Asthma Related to Choroidal Neovascularization?

Cited by 16 publications

References 35 publications

Associations of systemic, serum lipid and lipoprotein metabolic pathway gene variations with polypoidal choroidal vasculopathy in China

Associations of systemic, serum lipid and lipoprotein metabolic pathway gene variations with polypoidal choroidal vasculopathy in China

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

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