QM107, a novel CD148 (RTP Type J) activating peptide therapy for treating neovascular age-related macular degeneration.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Samantha Arokiasamy, Michaela J M Balderstone, Faheem Shaik, Enrico Cristante, Thomas C Moseley, Akshay Madoo, Matteo Rizzi, James W Bainbridge, Konstantin Tsoyi, Ivan O Rosas, James R Whiteford, Giulia De Rossi
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引用次数: 0

Abstract

Background and purpose: Angiogenesis is a pathological component of neovascular age-related macular degeneration. Current therapies, although successful, are prone to high levels of patient non-response and a loss of efficacy over time, indicating the need to explore other therapeutic avenues. We have shown that an interaction between syndecan-2 and the tyrosine phosphatase receptor CD148 (RTP Type J) results in the ablation of angiogenesis. Here we exploit this pathway to develop a peptide activator of CD148 as a therapy for neovascular age-related macular degeneration.

Experimental approach: We tested a peptide (QM107) derived from syndecan-2 in a variety of angiogenesis models and a pre-clinical model of neovascular age-related macular degeneration. We assessed the toxicological and inflammatory profiles of QM107 and its stability in vitreous humour.

Key results: QM107 inhibits angiogenesis in ex vivo sprouting assays and disrupts endothelial microcapillary formation via inhibition of cell migration. QM107 acts through CD148, leading to changes in GSK3A phosphorylation and β1 integrin activation. QM107 elicits a negligible inflammatory response and exhibits limited toxicity in cultured cells, and is stable in vitreous humour. Finally, we show proof of concept that QM107 blocks angiogenesis in vivo using a model of neovascular age-related macular degeneration.

Conclusion and implications: We have developed a CD148 activating peptide which shows promise in inhibiting angiogenesis in models of neovascular age-related macular degeneration. This treatment could either represent an alternative or augment existing therapies, and owing to its distinct mode of action be used in patients who do not respond to existing treatments.

用于治疗新生血管性老年黄斑变性的新型 CD148(RTP J 型)激活肽疗法 QM107。
背景和目的:血管生成是新生血管性老年黄斑变性的病理组成部分。目前的治疗方法虽然成功,但容易导致患者出现高水平的无应答,而且随着时间的推移,疗效会逐渐减弱,这表明有必要探索其他治疗途径。我们已经证明,辛迪加-2 和酪氨酸磷酸酶受体 CD148(RTP J 型)之间的相互作用会导致血管生成的消减。在此,我们利用这一途径开发了一种 CD148 多肽激活剂,用于治疗新生血管性老年黄斑变性:实验方法:我们在多种血管生成模型和新生血管性老年黄斑变性临床前模型中测试了一种源自辛迪加-2的多肽(QM107)。我们评估了QM107的毒理学和炎症特征及其在玻璃体液中的稳定性:主要结果:QM107在体外发芽试验中抑制血管生成,并通过抑制细胞迁移破坏内皮微毛细血管的形成。QM107通过CD148发挥作用,导致GSK3A磷酸化和β1整合素活化发生变化。QM107 在培养细胞中引起的炎症反应可忽略不计,毒性有限,在玻璃体液中也很稳定。最后,我们用一个新生血管性老年黄斑变性模型证明了 QM107 在体内阻断血管生成的概念:我们开发的 CD148 激活肽有望在新生血管性老年黄斑变性模型中抑制血管生成。这种疗法可以替代或增强现有疗法,而且由于其独特的作用模式,可用于对现有疗法无效的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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