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

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