Plaque, Atherosclerotic

Scientists report that a gene previously implicated in the development of atherosclerotic lesions in coronary arteries could be key to understanding why many people don't benefit from the most used therapy for neovascular age-related macular degeneration (AMD), a leading cause of blindness. Medical College of Georgia scientists report that a gene previously implicated in the development of atherosclerotic lesions in coronary arteries could be key to understanding why many people don't benefit from the most used therapy for neovascular age-related macular degeneration (AMD), a leading cause of blindness. AMD is a condition characterized by abnormal blood vessel growth in the back of the eye. It is highly prevalent in the elderly and people with diabetes, obesity, and many other chronic metabolic diseases. Excessive vascular growth damages the macula, the part of the eye that translates light into image signals. Anti-VEGF therapy, which blocks vascular endothelial growth factor and keeps excessive blood vessel growth at bay, is usually the first line of defense. But that treatment only works well for around a third of patients suffering from this form of AMD, says Dr. Yuqing Huo, MD, PhD, the Director of the Vascular Inflammation Program at MCG's Vascular Biology Center. "The reason is that the excess vasculature is often accompanied by the growth of fibroblast cells," he says. Collagen and many other proteins produced by these fibroblast cells accumulate outside of the vascular cells and eventually lead to fibrosis or scarring in the eye. This keeps the excess vasculature from being suppressed by anti-VEGF treatments. "We show, for the first time in this study, that many fibroblast cells are actually produced by these excessive endothelial cells. We must find a way to prevent this from happening," Huo says. He and his team believe the answer lies in targeting the adenosine receptor 2A (Adora2a) -- a G-protein-coupled adenosine receptor found in high levels in the brain, immune cells, and blood vessels. Adora2a has been reported to be crucial in modulating inflammation, myocardial oxygen consumption, and coronary blood flow. Adenosine, a metabolite produced by cells under conditions of stress, injuries, and lack of oxygen, can activate Adora2a to protect our body from injury. But in excess, adenosine can lead to excessive blood vessel growth. In their current research, Huo and his colleagues found a high-level or persistent adenosine-activated Adora2a signal could transform endothelial cells, the luminal cells of the vasculature, into activated fibroblast cells and, eventually, cause fibrosis. Huo and his colleagues hypothesize that blocking this receptor can prevent that from happening. Using genetically engineered mice that develop fibrosis in the backs of their eyes, researchers delivered an Adora2a agonist (KW6002), which binds to the receptor and blocks its function. "We also studied mice that had Adora2a removed from only the vascular endothelial cells," says Qiuhua Yang, PhD, a postdoctoral fellow with Huo and the first author on this study. "All of these mice demonstrated decreased fibrosis in the eye." These novel findings were reported and recently selected as the cover image for Science Translational Medicine. "We have previously demonstrated that blocking Adora2a can reduce excessive blood vessel growth, which happens in the early stages of AMD," says Yongfeng Cai, PhD, a postdoctoral fellow in Huo's lab and a member of the research team. They now have an eye toward generating an antibody that could recognize Adora2A. "The antibody could be delivered via an injection to the back of the eyes, an approach often used in eye clinics, to block the activation of adenosine to Adora2A," Huo says. "An antibody could really block both excessive blood vessel growth, the early stage of AMD, and fibrosis, the late stage of AMD. Our findings indicate that blocking Adora2a can certainly target multiple stages of this disease, which might be much more efficient than current treatments." This research was supported by a National Institutes of Health K99 award to Dr. Qiuhua Yang and funds from the National Eye Institute.

Following favorable FDA feedback for the treatment of liver disease, the company is preparing further pre-IND meetings with the FDA for the treatment of atherosclerosis and familial hypercholesterolemia SYRACUSE, NY / ACCESSWIRE / April 2, 2024 / Repair Biotechnologies, Inc. ( ) announced today that its lipid nanoparticle (LNP)/messenger RNA (mRNA) therapy has rapidly reversed the progression of atherosclerosis in mouse models applicable to both the rare genetic condition of familial hypercholesterolemia as well as atherosclerosis in the broader population. Repair Biotechnologies develops gene therapies based on the proprietary Cholesterol Degrading Platform (CDP) that safely break down excess free cholesterol inside cells. Excess free cholesterol is toxic to cells and contributes to the development of numerous conditions, including atherosclerosis and metabolic dysfunction-associated steatohepatitis (MASH). Established therapies that reduce LDL-cholesterol in the bloodstream have little effect on intracellular free cholesterol. "Unfortunately statins and PCSK9 inhibitors that reduce LDL-cholesterol in the blood exhibit little ability to reduce the size of established atherosclerotic lesions," said Mourad Topors, Chief Scientific Officer at Repair Biotechnologies. "Our studies in severely atherosclerotic mice demonstrate that LDL-cholesterol is the wrong target if the goal is the outright regression of plaque and dramatic reduction in risk of cardiovascular events. Instead, clearance of intracellular free cholesterol can potentially achieve these goals." Repair Biotechnologies scientists treated atherosclerotic APOE-null mice and LDLR-null mice over a period of six weeks with a CDP LNP-mRNA therapy, expressing therapeutic proteins that safely break down toxic free cholesterol in cells. APOE-null mice are a widely used, consensus model for atherosclerosis in the general population, while LDLR-null mice are the model for homozygous familial hypercholesterolemia, a genetic condition in which the LDLR gene suffers a loss of function mutation and which is characterized by greatly accelerated atherosclerosis. Both mouse models exhibited a dramatic reversal of atherosclerosis. Plaque in the aortic root of APOE-null mice exhibited a 19% drop in plaque lipids and a corresponding 23% increase in plaque collagen, indicating stabilization of soft, lipid-laden plaque that is prone to rupture. In LDLR-null mice, plaque obstruction of the aortic root was reduced by 17%, while treated mice exhibited a greatly improved capacity to run on a treadmill, a measure of cardiovascular health. "Our new results in atherosclerotic mice are as impressive as the results we achieved in mouse models of MASH," said Reason, co-founder and CEO of Repair Biotechnologies. "We are preparing for mid-2024 pre-IND meetings with the FDA for treatment of the rare genetic condition of homozygous familial hypercholesterolemia, as well as the treatment of atherosclerosis more generally. Our LNP-mRNA therapy is applicable in principle to the reversal of all forms of atherosclerosis." In high-fat diet mouse models of MASH, Repair Biotechnologies scientists have demonstrated as much as a 44% reduction in measures of liver fibrosis following eight weeks of CDP LNP-mRNA treatment. In March 2024, Repair Biotechnologies received favorable and comprehensive pre-IND feedback from the FDA. The company leadership looks forward to bringing this treatment to the clinic. Contact Information Reason CEO and Co-Founder press@repairbiotechnologies.com +1 315-299-2407 SOURCE: Repair Biotechnologies, Inc. View the original press release on newswire.com.

ADC研发，早已内卷成了麻花。医药寒冬下，还有哪些研发机会？siRNA或是不错的突破方向。随着小核酸药物成为近年来研发热点之一，其类别ASO、siRNA、aptamer等研发方向开始发力，以品种数量来看，siRNA逐渐成为研发界新宠。01上市6款，临床≥II期数十款与传统小分子和抗体相比，siRNA关联独特的疾病靶点、开发成功率高、开发时间短、并可基于技术平台进行药物开发。目前，全球有100多家公司从事siRNA领域的研究，其中约30家专门从事siRNA药物的开发。截至2023年，已有6种siRNA药物获批上市，其中5款来自于Alnylam。据Alnylam官网介绍，成立于2002年的Alnylam开发了全球首个获批上市的RNAi治疗药物ONPATTRO®（patisiran），后相继开发了GIVLAARI®（givosiran）、OXLUMO®（lumasiran）、Leqvio®（inclisiran）、AMVUTTRA®（vutrisiran）等，该公司当前重点专注于遗传疾病、心脏代谢疾病、传染病、中枢神经系统和眼部疾病等适应症领域。图1 Alnylam公司公布的药物研发管线图片来源：https://www.alnylam.com/alnylam-rnai-pipeline另，有文献报道，截至到2023年8月，全球有15个正在研究的siRNA药物处于临床2期或以上阶段，适应症主要集中于遗传性疾病、罕见病、并向其他常见疾病拓展（如代谢性疾病、心血管疾病、乙型肝炎、癌症等）。如，ALN-AGT（NCT04936035，NCT05103332）目前正在开发用于治疗高血压，并已进入II期临床。Olpasiran（NCT05581303）旨在治疗动脉粥样硬化斑块，目前正在进行III期临床。SLN360（NCT05537571）是一种降脂siRNA，已进入II期。RBD1016（NCT05961098）是一种用于治疗乙型肝炎的N-乙酰半乳糖胺（GalNAc）偶联siRNA，将在欧洲开始II期临床试验。STP705和STP707由两种靶向转化生长因子-β1（TGF-β1）和环氧合酶-2（COX-2）的siRNA组成，并以肽纳米颗粒（PNPs）的形式开发；STP705局部给药于病变组织，用于治疗原位鳞状细胞癌（NCT04844983，2期）和基底细胞癌（NCT04669808，2期），而STP707（NCT05037149，1期）为静脉注射给药，用于治疗多种实体瘤和纤维化性肝脏疾病，如原发性硬化性胆管炎。图2 获批上市&临床≥II期siRNA疗法图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.00502国内药企对siRNA的青睐据公开信息统计，国内药企在siRNA方向的产品布局，已有＞20款品种通过引进和自研的方式进行开发，最高临床阶段为临床II期。另，在刚刚过去的2023年，就有多个品种获得国内临床默示许可，具体如：君实生物与润佳医药共同研发的靶向血管生成素样蛋白3（ANGPTL3）siRNA药物JS401，拟用于治疗高脂血症。杭州舶临医药科技有限公司自主研发的siRNA新药BW-00163，拟用于治疗高血压；另一款siRNA新药BW-00112，拟用于治疗血脂异常；再一款siRNA新药BW-20805，拟用于治疗遗传性血管性水肿（HAE）。圣因生物自主研发的一款靶向肝细胞PCSK9的siRNA-GalNAc结合物SGB-3403，拟用于治疗高胆固醇血症、混合型血脂异常以及动脉粥样硬化性心血管疾病。正大天晴自主研发的一种靶向乙型肝炎病毒（HBV）的siRNA药物TQA3038，拟用于治疗慢性乙型肝炎。靖因药业开发的一款siRNA药物SRSD101，能特异性肝靶向PCSK9，临床拟用于治疗原发性高胆固醇血症；另一款siRNA药物SRSD107，临床拟用于预防或治疗血栓栓塞性疾病。石药集团自主研发的一款通过偶联GalNAc实现肝脏靶向递送的siRNA药物SYH2053，临床拟用于治疗成人原发性高胆固醇血症或混合型血脂异常。大睿生物自主研发的PCSK9靶向双链siRNA药物RN0191，临床拟用于治疗成人原发性高胆固醇血症（家族性和非家族性）或混合型血脂异常。03siRNA当前存在的技术痛点、解决方向尽管siRNA药物研究取得了重大进展，且国内药企对此青睐有加，但仍存在一些需要克服的关键挑战，有文献对此归纳为3个“E”挑战（进入-Entry、逃逸-Escape、疗效-Efficacy），并认为上述3点是限制siRNA临床开发的3个关键问题。➣进入挑战（有针对性的积累和细胞摄取）第一个挑战是在靶器官/组织中实现siRNA的有效富集和有效内化到目标靶细胞中。siRNA由于分子相对较大和阴离子电荷特性，未经修饰的裸siRNA表现出低生物利用度，且半衰期短至几分钟。同时，siRNA可以被存在于血浆、组织和细胞质中的核酸酶或磷酸酶迅速降解。尽管siRNA可以被动地在肝脏或肿瘤组织等多孔部位积累，但将这些治疗药物输送到优先吸收这些分子的器官以外的身体其他部位，以及BBB的有效跨膜，仍然面临着巨大的挑战。➣逃逸挑战（内体和溶酶体逃逸）第二个挑战是如何实现有效的内体和溶酶体逃逸。虽然siRNA可以通过内吞作用进入细胞，但只有不到1%的siRNA能够从内吞体逃逸，其中被动逃逸率小于0.01%。ASGPR（人去唾液酸糖蛋白受体）略不同，其肝细胞表达水平约为500000或更高，回收时间小于20分钟。治疗过程中，肝细胞细胞质中可以积累足够的GalNAc-siRNA偶联物，以达到治疗水平；但除了肝细胞外，对于其他类型的细胞，siRNA逃逸仍然是一个未解决的问题。➣疗效挑战（药物体内疗效）第三个挑战是需要良好的体内稳定性、持久的效果和安全性。利用病毒载体在体内传递核酸存在一定的毒副作用，化学合成的载体系统如阳离子脂质和大多数无机纳米颗粒也可能在体内诱导细胞凋亡和炎症。现，化学修饰已被广泛用于增强siRNA的稳定性，减少/消除脱靶效应和免疫原性，从而提高siRNA的“疗效”。通过复杂的修饰，siRNA已经成功实现了99%的基因沉默并在体内持续存在，可以实现低剂量的季度、半年甚至每年给药。然而，修饰诱导的稳定性和特异性增强可能会降低沉默活性或引起意想不到的不良反应。图3 限制siRNA临床开发的3个“E”挑战图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.005针对上述3个挑战，业界也正在逐点进行问题的解决，如进一步的结构修饰，这包括开发新的化学修饰单体、修饰模式和RNAi触发结构。传统的siRNA修饰主要包括2'-OMe、2'-F、PS，而新的修饰单体和修饰模式的发展将进一步完善siRNA的药代动力学和安全性。如，新型单体如乙二醇核酸(GNA)、5'-(E)-乙烯基膦酸盐[5'-(E)-VP]，新型RNAi触发结构如sciRNAs，不对称siRNA和二价siRNA骨架等。同时，siRNA的设计和修饰正在通过AI算法来实现。再如，开发一些独特的递送系统。虽然各种纳米材料如LNPs、聚合物、无机纳米颗粒和外泌体已经被开发成siRNA载体，但它们的负载能力、稳定性、安全性和有效性仍然存在局限性。未来的基础研究大体还是侧重于优化这些载体的理化性质，如与配体共价连接，这些配体包括小分子、脂质、多肽、抗体、糖、非编码RNA等，并基于此进一步形成靶向。图4 规避三个“E”挑战的策略和方法图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.00504结语siRNA自首款产品上市至今，较另一大类小核酸药物ASO，时间不长，相对具有更大的开发空间和潜力，国内药企也是纷纷将资源投入于此。但客观讲，基于该领域已形成的现有技术背景和现可以实现的技术特征如靶向、多途径给药、强效持久、低剂量、总体安全性等，国内企业目前大都处于跟进的状态，离“质”的突破尚需时间。同时，还需要注意其他类别小核酸药物的开发，防止形成技术方面总体被覆盖的可能性。参考来源：1.Trends in Molecular Medicine,January 2024,Vol.30,No.1.doi.org/10.1016/j.molmed.2023.10.0052.https://www.alnylam.com/声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 金银花转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是昨天最受欢迎的文章哦