Open Label Extension (OLE) for the Patients Treated in the ISD002-P144-07 Study With P144 Topical Adminsitration for Skin Fibrosis in Patients With Systemic Sclerosis

Transforming growth factor-beta 1 is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts(25, 26). Activation of TGF-beta receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-beta 1 i one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-beta1 mRNA and protein levels has been described in these processes. Peptide 144 (P144)is a acetic salt of a 14mer peptide from human TGF-beta1 type III receptor (betaglycan). P144 TGF-beta1-inhibitor has been specifically designed to block the interaction between TGF-beta1 and TGF-beta1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated sucutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The aim of the study is to asses the long-term safety of topical application of P144 cream in the treatment of skin fibrosis in patients with systemic sclerosis in an extension open-label treatment period of 6 additional months.

开始日期2008-07-01

申办/合作机构

ISDIN SA

[+1]

NCT00574613 / Completed临床2期

Phase II, Multicenter, Randomized, Double-blind, Intraindividually Placebo Controlled Clinical Trial, to Evaluate Efficacy and Safety of p144 Topical Administration for Skin Fibrosis in Patients With Systemic Sclerosis

Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to asses the efficacy and safety of topical application of P144 in the treatment of skin fibrosis in patients with systemic sclerosis.

开始日期2007-09-01

申办/合作机构

ISDIN SA

[+1]

NCT00656825 / Completed临床1期

Multicentre, Placebo-Controlled, Multi-Dosis, Phase I Clinical Trial to Evaluate the Tolerability and Bioavailability of TGF β1 Inhibitor Peptide 144 After Topical Administration in Healthy Volunteers.

Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to assess the tolerability and safety of topical application of P144 in healthy volunteers.

开始日期2007-03-01

申办/合作机构

ISDIN SA

[+1]

100 项与地司特肽相关的临床结果

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100 项与地司特肽相关的转化医学

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100 项与地司特肽相关的专利（医药）

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项与地司特肽相关的文献（医药）

2024-05-01·Arab Journal of Gastroenterology

TGF-β1 inhibitor P144 protects against benign restenosis after esophageal stenting through TGF-β1/Smads signaling pathway inhibition

Article

作者: Zhou, Wei-Zhong ; Zhou, Chun ; Wu, Jun-Zheng ; Yang, Wei ; Zhang, Jin-Xing ; Liu, Sheng ; Shi, Hai-Bin

BACKGROUND AND STUDY AIMSEsophageal restenosis is a serious complication after esophageal stent placement, which influences the clinical prognosis of stent implantation and the patient's quality of life. TGF-β1/Smads signaling pathway plays an important role in the development of the eosinophilic esophagitis and scar repair after skin trauma. However, the role of TGF-β1/Smads in the development of esophageal restenosis after esophageal stent placement remains unknown. Our study aimed to investigate whether TGF-β1/Smads plays an important role in the development of esophageal restenosis after esophageal stent, and whether the exogenous TGF-β1 inhibitor supplement could ameliorate the esophageal restenosis after esophageal stent.MATERIAL AND METHODSWe established the model of esophageal restenosis after esophageal stenting in rats, and determined the expression levels of TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation by immunochemistry (IHC), Western Blot and real time qPCR. Those all the indicators were also determined in esophageal fibroblast when exposed to rhTGF-β1 with or without TGF-β1 inhibitor P144.RESULTSThe serum level of IL-1β and TNFα were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. The TGF-β1/Smads signaling pathway and the relevant markers of fibroblast activation were significantly increased in stent implantation group compared to blank control group, and obviously ameliorated when treated with P144. Those all the indicators were significantly increased when exposed to rhTGF-β1, and obviously decreased when treated with P144.CONCLUSIONSTGF-β1 Inhibitor P144 could protect against benign restenosis after esophageal stenting by down-regulating the expression levels of relevant markers of fibroblast activation through TGF-β1/Smads signaling pathway inhibition, and may be used as a novel therapy for benign restenosis after esophageal stenting.

2023-01-01·Frontiers in oncology

PET imaging with [⁶⁸Ga]-labeled TGFβ-targeting peptide in a mouse PANC-1 tumor model.

Article

作者: Chen, Haojian ; Zheng, Qihuang ; Zhao, Hong ; Hu, Shan ; Li, Yong ; Zhang, Xichen

PurposeTransforming growth factor β (TGFβ) is upregulated in many types of tumors and plays important roles in tumor microenvironment construction, immune escape, invasion, and metastasis. The therapeutic effect of antibodies and nuclide-conjugated drugs targeting TGFβ has not been ideal. Targeting TGFβ with small-molecule or peptide carriers labeled with diagnostic/therapeutic nuclides is a new development direction. This study aimed to explore and confirm the imaging diagnostic efficiency of TGFβ-targeting peptide P144 coupled with [⁶⁸Ga] in a PANC-1 tumor model.ProceduresTGFβ-targeting inhibitory peptide P144 with stable activity was prepared through peptide synthesis and screening, and P144 was coupled with biological chelator DOTA and labeled with radionuclide [⁶⁸Ga] to achieve a stable TGFβ-targeting tracer [⁶⁸Ga]Ga-P144. This tracer was first used for positron emission tomography (PET) molecular imaging study of pancreatic cancer in a mouse PANC-1 tumor model.Results[⁶⁸Ga]Ga-P144 had a high targeted uptake and relatively long uptake retention time in tumors and lower uptakes in non-target organs and backgrounds. Target pre-blocking experiment with the cold drug P144-DOTA demonstrated that the radioactive uptake with [⁶⁸Ga]Ga-P144 PET in vivo, especially in tumor tissue, had a high TGFβ-targeting specificity. [⁶⁸Ga]Ga-P144 PET had ideal imaging efficiency in PANC-1 tumor-bearing mice, with high specificity in vivo and good tumor-targeting effect.Conclusion[⁶⁸Ga]Ga-P144 has relatively high specificity and tumor-targeted uptake and may be developed as a promising diagnostic tool for TGFβ-positive malignancies.

2022-10-01·Cell Proliferation

TGF‐β1 peptide‐based inhibitor P144 ameliorates renal fibrosis after ischemia–reperfusion injury by modulating alternatively activated macrophages

Article

作者: Ouyang, Qing ; Li, Delun ; Chen, Xiangmei ; Li, Lili ; Yuan, Siyu ; Zhang, Jian ; Tong, Yan ; Sang, Tian ; Wang, Chao ; Chang, Jiakai ; Li, Jijun ; Liu, Ran

AbstractObjectivesIschemia–reperfusion injury (IRI) is a major cause of chronic renal fibrosis. Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide‐based TGF‐β1 inhibitor P144 in IRI‐induced renal fibrosis and the underlying mechanism were analyzed.Materials and MethodsThe unilateral ischemia–reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio‐distribution of P144. The transwell assays were used to observe the migration of macrophages. RT‐qPCR and western blot were used to analyze TGF‐β1 signaling.ResultsP144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia–reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF‐β1‐Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF‐β1‐dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2‐like phenotype induced by TGF‐β1 in vitro, but showed no effect on their proliferation.ConclusionsOur study showed that the TGF‐β1 peptide‐based inhibitor P144 decreased renal fibrosis through the blockade of the TGF‐β1–Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI‐induced renal fibrosis.

100 项与地司特肽相关的药物交易

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外链

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
系统性硬皮病	临床2期	-	Digna Biotech SL	-
系统性硬皮病	临床2期	-	Flamel Technologies, Inc.	-
系统性硬皮病	临床2期	-	ISDIN SA	-
系统性硬皮病	临床2期	-	University of Navarra	-
纤维化	临床1期	德国	ISDIN SA	2008-07-01
纤维化	临床1期	西班牙	ISDIN SA	2008-07-01
纤维化	临床1期	意大利	Digna Biotech SL	2008-07-01
纤维化	临床1期	英国	Digna Biotech SL	2008-07-01
光化性角化病	临床前	欧洲	-	-
皮肤肿瘤	临床前	欧洲	-	-