ASC2

Initiated by the licensing of a Duke-NUS invention to Paratus, the two parties also signed an agreement to enable the potential development of other therapeutics from future collaborative research into bat immunology. SINGAPORE, 15 August 2023 – Duke-NUS and Paratus Sciences Corporation, a start-up headquartered in New York, today announced that they have signed two agreements to advance innovations in human health arising from research in bat immunology. The joint effort aims to translate insights about the biology of bats' unique resistance to disease into the development of human therapeutics, including therapeutics targeting infections and inflammation. In the first instance, Paratus will develop a new class of anti-inflammatory drugs under a license to commercialise a Duke-NUS invention based on findings summarised in a paper recently published in the journal Cell by Professor Wang Linfa and his team from Duke-NUS’ Emerging Infectious Diseases Programme. In this paper, Prof Wang and his team revealed that a bat protein called ASC2 is a powerful inhibitor of the bat’s inflammatory mechanism. The findings explain bats’ ability to avoid significant illness even when they are infected with viruses that can cause symptoms in humans. The license from Duke-NUS allows Paratus to develop drug candidates that could mimic the anti-inflammatory effect of ASC2. “The extreme stress that flying exerts on bats’ cells has forced them to evolve a unique inflammation-dampening resilience. This resilience is so effective that bats can carry dangerous viruses, including coronaviruses and viruses like Ebola, without falling sick,” said Prof Wang, one of the world’s leading experts in zoonotic diseases, bat immunology and pathogen discovery. “Our deep understanding of bat immunology provides a scientific foundation from which we can develop novel therapeutics. We are learning from bats to fight human diseases.” Paratus has established a subsidiary in Singapore (Paratus Sciences Singapore), headquartered at ClavystBio’s Node 1, a collaborative innovation space at Singapore Science Park. Paratus Sciences Singapore will collaborate with Duke-NUS, beyond the initial technology license, on a broader investigation of bat immunology for new insights with therapeutic potential. The collaboration will bring together the biological, genomics, bioinformatics expertise of both organizations and will leverage their resources and infrastructure to find new therapeutic opportunities right here in Singapore. Associate Professor Christopher Laing, Vice-Dean for Innovation and Entrepreneurship at Duke-NUS, said, “Close partnerships with industry partners, starting at the earliest stages of innovation and continuing as long-term collaborations, are essential for successful transition from the lab to the clinic. With Paratus, we will not only bring one of Prof Wang’s inventions closer to the market—and to patients—but will find new directions for innovative solutions based on his lab’s ground-breaking research.” “We are thrilled to be strengthening our relationship with Duke-NUS and its phenomenal scientists,” said Dr Phil Ferro, President of Paratus. “We believe the insights gleaned from the in-depth study of bat biology, as Professor Wang’s team has demonstrated, will unlock the ability to develop many novel therapeutics for unmet needs in human health.” Reference: Ahn, M., Chen, V.C.W., Rozario, P., Ng, W.L., et al. 2023. Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases. Cell. 2023; 186: 2144-2159.e22. DOI: 10.1016/j.cell.2023.03.036

在一项新的研究中，来自杜克-新加坡国立大学医学院的研究人员通过研究蝙蝠在没有明显疾病的情况下容纳病毒的不寻常能力，发现了一种可能开启对抗人类炎症性疾病的新策略的蛋白。相关研究结果发表在2023年5月1 在一项新的研究中，来自杜克-新加坡国立大学医学院的研究人员通过研究蝙蝠在没有明显疾病的情况下容纳病毒的不寻常能力，发现了一种可能开启对抗人类炎症性疾病的新策略的蛋白。相关研究结果发表在2023年5月11日的Cell期刊上，论文标题为“Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases”。 论文共同通讯作者、杜克-新加坡国立大学医学院新兴传染病项目的Wang Lin-Fa教授说，“蝙蝠作为导致COVID-19大流行的SARS-CoV-2病毒的潜在宿主引起了极大的关注。但是，如果我们能够理解并利用它们如何实现这一目标，这种独特的容纳病毒但又能在病毒感染中存活的能力也可能对人类健康产生非常积极的影响。” 这项新的研究着重关注称为炎性体（inflammasome）的多蛋白复合物，这类蛋白复合物这种复合物负责过度活跃的炎症，从而导致许多疾病中的严重症状。炎性体也与衰老过程中的功能衰退有关。 这些作者发现一种名为ASC2的蝙蝠蛋白具有抑制炎性体的强大能力，从而限制了炎症的发生。论文共同第一作者兼论文共同通讯作者Matae Ahn博士解释说，“这表明ASC2的高水平活性是蝙蝠控制炎症的一个关键机制，对它们的长寿命和作为病毒储存库的独特地位有影响。” 论文共同第一作者、杜克-新加坡国立大学医学院博士生Vivian Chen强调，这些作者能够通过展示这种蝙蝠蛋白在小鼠身上的有效性来证明它在人类身上的潜力。她阐述说，“在经过基因改造的小鼠中表达这种蝙蝠蛋白可以抑制炎症，并减少由多种诱因（包括病毒）驱动的疾病的严重性。” 对ASC2蛋白的详细研究发现这种蝙蝠蛋白分子中的四个氨基酸是使它比其相应的人类蛋白更有效地抑制炎症的关键。这为开发能够模拟这种蝙蝠蛋白的抗炎作用的药物提供了宝贵的见解。 图片来自Cell, 2023, doi:10.1016/j.cell.2023.03.036。 这些作者的下一步是研究他们的发现在治疗人类疾病方面的潜力。Wang教授说，“我们已根据这项研究申请了专利，并正在探索药物研发的商业合作。我们希望为炎性体驱动的人类疾病开发一类新的抗炎药物。” Wang教授坚信，现在是时候把重点放在使蝙蝠变得如此与众不同的更有前途的方面，“以帮助在未来对抗人类疾病”。 杜克-新加坡国立大学医学院研究高级副院长Patrick Casey教授对这项研究评论说，“即使COVID-19开始从公众的视线中退去，Wang教授和他的团队也继续通过对蝙蝠生物学的基础研究取得新的突破，产生了独特的见解，有可能加强全球大流行病的防范。这是基础科学研究为解决重大公共卫生挑战所带来的巨大价值的一个典型例子。”（生物谷 Bioon.com） 参考资料： Matae Ahn et al. Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases. Cell, 2023, doi:10.1016/j.cell.2023.03.036.

SINGAPORE, 12 May 2023 – By studying the unusual ability of bats to host viruses without significant illness, scientists at Duke-NUS Medical School have discovered a protein that could unlock new strategies for fighting inflammatory diseases in humans. “Bats have attracted great attention as a likely reservoir of the SARS-CoV-2 virus responsible for the COVID-19 pandemic,” said Professor Wang Lin-Fa, from Duke-NUS’ Emerging Infectious Diseases (EID) Programme, the senior author of the study published in the journal Cell. “But this unique ability to host yet survive viral infections could also have a very positive impact on human health if we can understand and exploit how they achieve this.” The research is focused on multi-protein complexes called inflammasomes that are responsible for the overactive inflammation that causes serious symptoms in many diseases. Inflammasomes are also implicated in functional decline in ageing. The Duke-NUS team discovered that a bat protein called ASC2 has a powerful ability to inhibit inflammasomes, thereby limiting inflammation. “This suggests that the high-level activity of ASC2 is a key mechanism by which bats keep inflammation under control, with implications for their long lifespan and unique status as a reservoir for viruses,” explained Dr Matae Ahn, first author and co-corresponding author of the study, who is an Adjunct Research Fellow with the EID Programme and the SingHealth Duke-NUS Medicine Academic Clinical Programme. Dr Ahn is also a full-time clinician in SingHealth’s Postgraduate Year One (PGY1) Residency Programme after graduating from Duke-NUS in 2022. Ms Vivian Chen, co-first author of the study and an MD-PhD candidate in Duke-NUS, highlighted that the team was able to demonstrate the potential for exploiting the powers of the bat protein in humans by showing it could also be effective in mice*. She elaborated, “Expression of the bat protein in genetically-modified mice dampened inflammation and reduced the severity of the diseases driven by various triggers, including viruses.” Examination of the ASC2 protein in detail identified four amino acids in the molecule that were key to making the bat protein more effective at dampening inflammation than its corresponding human protein. This provides valuable insight for the development of drugs that can mimic the anti-inflammatory effect of the bat protein. The next step for the team is to investigate the potential of their findings for treating humans. Prof Wang said: “We have filed patents based on this work and are exploring commercial partnerships for drug discovery. We are hoping to develop a new class of anti-inflammatory drugs for inflammasome-driven human diseases.” Prof Wang strongly believes that it is time to focus on the more promising aspects of what makes bats special “to help fight the human diseases of the future.” Duke-NUS’ Senior Vice-Dean for Research, Professor Patrick Casey, commented on the study, “Even as COVID-19 begins to recede from the public’s attention, Professor Wang and his team continue to break new ground with their basic research into bat biology, yielding unique insights that can potentially strengthen global pandemic preparedness. This is a prime example of the immense value basic scientific research brings to solving major public health challenges.” (Concept art representing the study and its findings developed by the study team) Flying in the starry night are our nocturnal and echo-locating bats, the only mammals capable of powered flight. The fire symbolises the inflammation driven by the activation of inflammasomes—multi-protein complexes that assemble inside cells in response to danger or microbial signals. Adaption to flight (a metabolically costly process) may have driven key changes in the bat's immune system that enable it to survive viral and other diseases that would kill other mammals. Among these key changes are differences in the highly expressed protein ASC2, a potent negative regulator of inflammasomes in bats and humans. In bats, however, the ASC2 protein has naturally evolved to dampen inflammation. This insight could lead to the development of novel therapeutics against inflammatory diseases. Credit: Qi Su * All work with laboratory animals in this study fully complied with policies and guidelines for the humane care and use of laboratory animals set forth by the Institutional Animal Care and Use Committee (IACUC). Reference: Ahn, M., Chen, V.C.W., Rozario, P., Ng, W.L., et al. 2023. Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases. Cell. 2023; 186: 2144-2159.e22. DOI: 10.1016/j.cell.2023.03.036