更新于：2024-11-01

PRG4 x IL-1RA

更新于：2024-11-01

基本信息

关联

项与 PRG4 x IL-1RA 相关的药物

GQ-501

靶点

IL-1RA x PRG4

作用机制

IL-1RA刺激剂 [+1]

在研机构

GeneQuine Biotherapeutics GmbH

原研机构

GeneQuine Biotherapeutics GmbH

在研适应症

骨关节炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PRG4 x IL-1RA 相关的临床结果

登录后查看更多信息

100 项与 PRG4 x IL-1RA 相关的转化医学

登录后查看更多信息

0 项与 PRG4 x IL-1RA 相关的专利（医药）

登录后查看更多信息

项与 PRG4 x IL-1RA 相关的文献（医药）

2019-02-01·Human Gene Therapy2区 · 医学

CombinatorialPrg4andIl-1raGene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis

2区 · 医学

Article

作者: Jayaram, Prathap ; Song, I-wen ; Cela, Racel ; Ruan, Merry Z. C. ; Gannon, Francis ; Jiang, Ming-Ming ; Dawson, Brian ; Chen, Yuqing ; Stone, Adrianne ; Grol, Matthew W. ; Lee, Brendan H. L.

Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone. Employing two surgical techniques to model mild, moderate and severe posttraumatic OA, we found that combined delivery of helper-dependent adenoviruses (HDVs), expressing IL-1Ra and PRG4, preserved articular cartilage better than either monotherapy in both models as demonstrated by preservation of articular cartilage volume and surface area. This improved protection was associated with increased expression of proanabolic and cartilage matrix genes together with decreased expression of catabolic genes and inflammatory mediators. In addition to improvements in joint tissues, this combinatorial gene therapy prolonged protection against thermal hyperalgesia compared to either monotherapy. Taken together, our results show that a combinatorial strategy is superior to monotherapeutic approaches for treatment of posttraumatic OA.

2011-04-01·Genetics Research4区 · 生物学

Identifying a major locus that regulates spontaneous arthritis in IL-1ra-deficient mice and analysis of potential candidates

4区 · 生物学

ArticleOA

作者: Shriner, Daniel ; Yan, Jian ; Jiao, Feng ; Stuart, John ; Gu, Weikuan ; Jiao, Yan ; Xiong, Qing ; Hasty, Karen

SummaryTo identify genetic loci that regulate spontaneous arthritis in interleukin-1 receptor antagonist (IL-1ra)-deficient mice, an F2 population was created from a cross between Balb/c IL-1ra-deficient mice and DBA/1 IL-1ra-deficient mice. Spontaneous arthritis in the F2 population was examined and recorded. Genotypes of those F2 mice were determined using microsatellite markers. Quantitative trail locus (QTL) analysis was conducted with R/qtlbim. Functions of genes within QTL chromosomal regions were evaluated using a bioinformatics tool, PGMapper, and microarray analysis. Potential candidate genes were further evaluated using GeneNetwork. A total of 137 microsatellite markers with an average of 12 cM spacing along the whole genome were used for determining the correlation of arthritis phenotypes with genotypes of 191 F2 progenies. By whole-genome mapping, we obtained QTLs on chromosomes 1 and 6 that were above the significance threshold for strong Bayesian evidence. The QTL on chromosome 1 had a peak near D1Mit55 and D1Mit425 at 82·6 cM. It may account for as much as 12% of the phenotypic variation in susceptibility to spontaneous arthritis. The QTL region contained 208 known transcripts. According to their functions, Mr1, Pla2g4a and Fasl are outstanding candidate genes. From microarray analysis, 11 genes were selected as favourable candidates based on their function and expression profiles. Three of those 11 genes, Prg4, Ptgs2 and Mr1, correlated with the IL-1ra pathway. Those genes were considered to be the best candidates.

Frontiers in Immunology2区 · 医学

Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs

2区 · 医学

ArticleOA

作者: Cabezas, Ralph ; Qadri, Marwa ; ElSayed, Sandy ; Elsaid, Khaled A ; Jay, Gregory D ; Schmidt, Tannin A

ObjectivesTo compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes.MethodsAcute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed.ResultsEnhanced phagocytic activation of gout monocytes under basal conditions (p<0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p<0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p<0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p<0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p<0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p<0.05).ConclusionsMSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.