VEGF x PDGFRβ

*仅供医学专业人士阅读参考 1961年，科学家首次描述了细胞衰老（senescence）的概念，这一机制在癌症、衰老和多种年龄相关疾病中起着至关重要的作用。此前的一些研究发现，通过遗传学或者药理学方法，消除以p16Ink4a（细胞周期蛋白依赖性激酶抑制蛋白）为标志物的衰老细胞，可以延长早衰小鼠的寿命，减轻衰老小鼠的年龄相关表型，改善多种年龄相关疾病。 然而，也有研究显示，完全清除衰老细胞并不是最佳策略，这些衰老细胞中可能仍有部分具有正常的生理功能性。因此，了解不同衰老细胞的病理生理作用，靶向性清除特定类型的衰老细胞，可能是更好的策略。 为此，中国科学院分子细胞科学卓越创新中心的周斌研究员带领研究团队在《细胞》杂志上发表了最新研究成果[1]，他们开发了一个包含三种p16Ink4a相关交叉遗传系统的体内遗传学工具集，可以追踪、消融和调控p16Ink4a+细胞。 以肝损伤和修复为例，研究人员发现，巨噬细胞和内皮细胞代表了不同的衰老细胞类型，清除p16Ink4a+巨噬细胞能够减轻肝细胞损伤，而清除p16Ink4a+内皮细胞则加重了肝损伤，另外，重编程p16Ink4a+内皮细胞显著减少了肝纤维化。这表明了p16Ink4a+衰老细胞的功能多样性，为未来开发细胞类型特异性的衰老细胞清除疗法提供了基础。 为了在单细胞水平上鉴定表达p16Ink4a的细胞类型，研究人员首先创建了一种新的荧光报告基因系p16-tdT，并分离小鼠胚胎成纤维细胞进行重复传代，诱导细胞衰老。随着细胞传代次数增加，表达tdT的细胞比例显著增加。与第二代相比，第六代和第七代细胞的p16蛋白水平也显著增加，这些细胞同样表达tdT，意味着p16-tdT能够反映p16的表达情况。 在老年小鼠中，p16Ink4a+细胞在不同器官中的身份是多样化的，例如大脑中的p16Ink4a+细胞主要是皮层神经元，而胰腺中是各种胰岛内分泌细胞，这些细胞有明显更强的衰老相关β半乳糖苷酶（SA-β-Gal）活性、更弱的增殖能力和更高的衰老相关分泌表型（SASP）因子表达，证实了它们的衰老细胞性质。 不同器官中主要的衰老细胞类型 肝纤维化是肌成纤维细胞活化的结果，细胞衰老与肝纤维化具有因果关联。在诱导肝纤维化的小鼠中，研究人员也观察到了部分位置的tdT富集，与SA-β-Gal相一致。在肝脏不同类型的细胞中，成纤维细胞、内皮细胞和巨噬细胞的一组呈p16Ink4a+，由于衰老成纤维细胞与肝损伤和疾病的研究已经相当深入，研究人员决定把目光放在内皮细胞与巨噬细胞上。 为了检测不同类型的p16Ink4a+细胞在肝损伤和修复中的最终命运，研究人员开发了一个名为衰老细胞脉冲追踪示踪器（Sn-pTracer）的遗传系统。 对巨噬细胞和内皮细胞的追踪显示，肝损伤后，p16Ink4a+巨噬细胞显著增加，但在修复后大量凋亡，而p16Ink4a+内皮细胞在损伤后增加的同时，在修复阶段也有大量存活，表明细胞衰老可能是一种细胞周期停滞的暂时形式，根据细胞类型决定是否可逆。 在接下来的实验中，由于Sn-pTracer需要对小鼠进行频繁的处理，并且可能对小鼠有害，研究人员进行了优化，开发了衰老细胞Cre诱导示踪器（Sn-cTracer），使用白喉毒素处理小鼠，相比对照组的磷酸缓冲液，显著减少了p16Ink4a+巨噬细胞，同时，小鼠的肝纤维化面积显著缩小，纤维化标志物PDGFRα、PDGFRβ和肌间线蛋白水平也显著下降。 纤维化标志物水平下降（M）和肝纤维化减轻（N） 研究人员使用同样的方法对p16Ink4a+内皮细胞进行了检测，内皮细胞减少后，小鼠的肝纤维化恶化，PDGFRα、PDGFRβ和肌间线蛋白水平也有相应的增加。也就是说，p16Ink4a+内皮细胞在功能上是限制肝损伤和纤维化的，p16Ink4a+巨噬细胞则刚好相反。 消除p16Ink4a+巨噬细胞后，小鼠肝纤维化的免疫微环境发生变化，包括T细胞活化、增殖、分化和参与免疫反应的淋巴细胞活化增强，流式细胞术也观察到T细胞和NK细胞的比例显著增加，它们在肝纤维化的限制和消退中起重要作用，因此，特异性消除p16Ink4a+巨噬细胞可能通过促进T细胞的生长和活化限制了肝纤维化。 肝纤维化免疫微环境中T细胞和淋巴细胞变化 相反，消除p16Ink4a+内皮细胞后，小鼠肝纤维化的免疫微环境向促纤维化的方向发生了转变。 通过RNA测序，研究人员还发现，p16Ink4a+内皮细胞中Kdr的表达显著下降，Kdr是血管再生和肝脏修复过程中VEGF信号通路的关键受体。鉴于VEGF信号的激活可以改善内皮细胞功能和肝脏的年龄相关变化，研究人员又设计了可以特异性地调控p16Ink4a+细胞中基因表达的衰老细胞基因操作示踪器（Sn-gTracer）。 利用Sn-gTracer过表达Kdr使得p16Ink4a+内皮细胞重编程后，小鼠的肝纤维化得到了显著改善。 综上所述，不同类型的衰老细胞在器官和组织中具有不同的功能，基于细胞类型的特异性衰老细胞清除可能才是改善年龄相关疾病的关键所在，为衰老细胞清除疗法提供了新的研究工具和研究方向。 参考文献： [1] https://www.cell.com/cell/fulltext/S0092-8674(24)01069-9 本文作者 | 应雨妍

Novartis recently notified Allarity Therapeutics that it was breaking off their licensing agreement for dovitinib due to nonpayment. Allarity gained exclusive rights to dovitinib through the 2018 deal, but the termination now leaves the status of the pan-tyrosine kinase inhibitor uncertain.Novartis had conducted a Phase III trial of dovitinib, but reported in 2013 that despite showing activity, the drug was no better than Bayer's Nexavar (sorafenib) in treating patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. The Swiss drugmaker had also run Phase II studies in breast, liver and endometrial cancer and gastrointestinal stromal tumours.Allarity said it received notice from Novartis on January 26 that it was cancelling their agreement based on "material breach for lack of financial payment." The termination took effect that day.Allarity was already running a Phase Ib combination study of dovitinib along with its lead asset stenoparib, a dual PARP and Tankyrase inhibitor. It was planning to begin testing dovitinib with a PD-1 inhibitor in the first half of this year as well.In November, Allarity disclosed in a US securities filing that it had missed license payments to Novartis last year, but that it was attempting to "cure this breach…subject to availability of funds and/or continue working with Novartis on an alternate payment structure."Meanwhile, the company said it is committed to advancing stenoparib, which is currently also in Phase II testing as monotherapy for ovarian cancer. In December, Allarity shares gained 15% after it reported data from five evaluable patients, with one experiencing a complete response while the others demonstrated stable disease.The company also announced late last year that James Cullem was no longer its CEO, and that he was being replaced on an interim basis by co-founder Thomas Jensen.

The prevalence of diabetic retinopathy has been rising over the past few years, which prompts the growing demand for treatment options. The increasing prevalence of diabetic retinopathy and the growing research and development activities to develop novel therapies to treat diabetic retinopathy to drive the market. The companies developing the potential therapies in the last stage of development include Roche, Kodiak Sciences, Novartis, and several others. LAS VEGAS, May 29, 2023 /PRNewswire/ -- DelveInsight's ' Diabetic Retinopathy Pipeline Insight – 2023 ' report provides comprehensive global coverage of pipeline diabetic retinopathy therapies in various stages of clinical development, major pharmaceutical companies working to advance the pipeline space and future growth potential of the diabetic retinopathy pipeline domain. Key Takeaways from the Diabetic Retinopathy Pipeline Report DelveInsight's diabetic retinopathy pipeline report depicts a robust space with 50+ active players working to develop 55+ pipeline therapies for diabetic retinopathy treatment. Key diabetic retinopathy companies such as Kodiak Sciences, Novartis, Regenxbio Inc., OcuTerra Therapeutics, Ocular Therapeutix, Bayer, RemeGen, Roche, Ocuphire Pharma, Adverum Biotechnologies, Boehringer Ingelheim, Palatin Technologies, Valo Health, EyePoint Pharmaceuticals, Kubota Vision, MingSight Pharmaceuticals, Oxurion, Aerie Pharmaceuticals, AsclepiX Therapeutics, Ocugen, Ashvattha Therapeutics, Stealth BioTherapeutics, and others are evaluating new diabetic retinopathy drugs to improve the treatment landscape. Promising diabetic retinopathy pipeline therapies in various stages of development include KSI-301, Brolucizumab, RGX 314, OTT-166, OTX-TKI, Runcaciguat, RC 28 E, RG7774, APX3330, ADVM-022, Faricimab, BI 764524, PL8331, OPL-0401, EYP-1901, emixustat hydrochloride, MS-553, THR-149, AR-13503, AXT107, OCU200, D 4517.2, Elamipretide, and others. In May 2023, Oculic Holding AG announced positive top-line results from Stage 1 of its Phase III DIAMOND trial of OCS-01 eye drops in diabetic macular edema (DME). According to the company, the DIAMOND trial in diabetic macular edema with topical OCS-01 met its stage 1 objective of validating the loading and maintenance dosing regimen designed to optimize OCS-01 efficacy potential with robust statistical significance. In April 2023, Palatin Technologies announced The International Journal of Molecular Sciences published a manuscript, "Stimulating the Melanocortin System in Uveitis and Diabetes Preserves the Structure and Anti-Inflammatory Activity of the Retina" by Tat Fong Ng and Andrew W. Taylor from Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, in Boston, Massachusetts. The manuscript summarizes data demonstrating the effects of PL8331 in two mouse models of retinal disease, experimental autoimmune uveoretinitis (EAU) and diabetic retinopathy (DR). Palatin and the National Institute of Health (NIH) and the Massachusetts Lions Eye Research Foundation provided funding for the study. In February 2023, Ocugen announced that it had submitted an Investigational New Drug application (IND) with the US Food and Drug Administration (FDA) to initiate a Phase 1 clinical trial of OCU200, a fusion protein with a distinct mechanism of action (MOA), for the treatment of diabetic macular edema (DME). This regulatory milestone fulfills the Company's commitment to file the IND for OCU200 within the first quarter of 2023. In January 2023, Ocuphire Pharma announced topline efficacy and safety results from its ZETA-1 Phase II trial evaluating oral APX3330 for the treatment of diabetic retinopathy (DR). Oral APX3330 demonstrated favorable safety and tolerability allowing for a potential attractive non-invasive option for protection of vision in both eyes in DR patients. In May 2022, EyePoint Pharmaceuticals announced the EYP-1901 license to Betta Pharmaceuticals, to develop and commercialize EYP-1901 in China, Hong Kong, Macau, and Taiwan. EyePoint retains all rights for EYP-1901 in the rest of the world and expands its exclusive rights to local delivery of vorolanib for the treatment of all ophthalmic diseases, including diabetic macular edema (DME). Request a sample and discover the recent advances in diabetic retinopathy drug treatment @ Diabetic Retinopathy Pipeline Report The diabetic retinopathy pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage diabetic retinopathy drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the diabetic retinopathy clinical trial landscape. Diabetic Retinopathy Overview Diabetic retinopathy is a microvascular condition caused by diabetes mellitus's long-term effects. Diabetic retinopathy can cause vision-threatening retinal damage, eventually leading to blindness. It is found in one-third of patients with diabetes and is linked to an increased risk of life-threatening systemic vascular consequences such as stroke, coronary heart disease, and heart failure. Diabetic retinopathy affects an estimated 40% (8% for vision-threatening retinopathy) of people with type 2 diabetes and 86% (42%) of people with type 1 diabetes in the United States. The keys to avoiding diabetic retinopathy blindness are early detection and appropriate intervention. Several large studies have found that the onset of diabetic retinopathy does not usually occur within the first 5 years of type 1 diabetes diagnosis. In contrast, the onset of type 2 diabetes is frequently more subtle, and as a result, retinal damage may be evident at the time of diagnosis. As a result, screening for diabetic retinopathy is advised in type 2 diabetics at the time of diagnosis. Find out more about drugs for diabetic retinopathy @ New Diabetic Retinopathy Drugs A snapshot of the Diabetic Retinopathy Pipeline Drugs mentioned in the report: Learn more about the emerging diabetic retinopathy pipeline therapies @ Diabetic Retinopathy Clinical Trials Diabetic Retinopathy Therapeutics Assessment The diabetic retinopathy pipeline report proffers an integral view of diabetic retinopathy emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Diabetic Retinopathy Pipeline Report Coverage: Global Diabetic Retinopathy Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Diabetic Retinopathy Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Diabetic Retinopathy Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous, Parenteral, Topical Diabetic Retinopathy Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Diabetic Retinopathy Therapeutics Assessment By Mechanism of Action: Vascular endothelial growth factors inhibitors, Angiogenesis inhibitors, Vascular endothelial growth factor A inhibitors, Gene transference, Integrin alphaVbeta3 antagonists, Integrin alphaVbeta6 inhibitors, Integrin alphavbeta8 inhibitors, Platelet-derived growth factor beta receptor antagonists, Protein tyrosine kinase inhibitors, Proto oncogene protein c-kit inhibitors, Vascular endothelial growth factor receptor 3 antagonists, Vascular endothelial growth factor receptor-1 antagonists, Vascular endothelial growth factor receptor-2 antagonists, Guanylate cyclase stimulants, APEX1 protein inhibitors, DNA apurinic apyrimidinic site lyase inhibitors Key Diabetic Retinopathy Companies: Kodiak Sciences, Novartis, Regenxbio Inc., OcuTerra Therapeutics, Ocular Therapeutix, Bayer, RemeGen, Roche, Ocuphire Pharma, Adverum Biotechnologies, Boehringer Ingelheim, Palatin Technologies, Valo Health, EyePoint Pharmaceuticals, Kubota Vision, MingSight Pharmaceuticals, Oxurion, Aerie Pharmaceuticals, AsclepiX Therapeutics, Ocugen, Ashvattha Therapeutics, Stealth BioTherapeutics, and others. Key Diabetic Retinopathy Pipeline Therapies: KSI-301, Brolucizumab, RGX 314, OTT-166, OTX-TKI, Runcaciguat, RC 28 E, RG7774, APX3330, ADVM-022, Faricimab, BI 764524, PL8331, OPL-0401, EYP-1901, emixustat hydrochloride, MS-553, THR-149, AR-13503, AXT107, OCU200, D 4517.2, Elamipretide, and others. Dive deep into rich insights for new drugs for diabetic retinopathy treatment; visit @ Diabetic Retinopathy Medications Table of Contents For further information on the diabetic retinopathy pipeline therapeutics, reach out @ Diabetic Retinopathy Drug Treatment Related Reports Diabetic Retinopathy Market Diabetic Retinopathy Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key diabetic retinopathy companies, including Genentech, Inc., Regeneron Pharmaceuticals, Roche, Opthea Limited, Regenxbio, Kodiak Sciences Inc, Ocuphire Pharma, Eisai Co Ltd, Apexian Pharmaceuticals, Oculis, among others. Diabetic Retinopathy Epidemiology Forecast Diabetic Retinopathy Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and diabetic retinopathy epidemiology trends. Proliferative Diabetic Retinopathy Pipeline Proliferative Diabetic Retinopathy Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key proliferative diabetic retinopathy companies, including Kubota Vision, among others. Diabetic Neuropathy Pipeline Diabetic Neuropathy Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key diabetic neuropathy companies, including Goldfinch Bio, Novartis, Serodus, CURACLE, Daiichi Sankyo, NeuroBo Pharmaceuticals, Dong-A Pharmaceutical, among others. Diabetic Neuropathy Market Diabetic Neuropathy Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key diabetic neuropathy companies, including Goldfinch Bio, Novartis, Serodus, CURACLE, Daiichi Sankyo, NeuroBo Pharmaceuticals, Dong-A Pharmaceutical, among others. Related Healthcare Services Healthcare Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . 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