When the body detects a pathogen, such as bacteria or viruses, it escalates the immune system’s response to fight that invader. In some people, the immune system overreacts, which leads to an overactive immune response that causes the body to infect itself, which in some cases may result in death.
Now, scientists from Nanyang Technological University, Singapore (NTU Singapore) have created a compound that can help reduce this hyperactivity without harming the entire body’s immune response.
An overactive immune system leads to many autoimmune disorders – when the immune system mistakenly attacks healthy tissues – such as rheumatoid arthritis and type 1 diabetes. Recently, it has also been linked to severe COVID-19 infection, in which the signaling proteins of the immune system rise to dangerous levels, resulting in damage to the body’s cells.
Designed by NTU’s research team, this compound, called ASO-1, targets tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family of enzymes that play a key role in regulating the body’s immune response. A recent study led by the University of Edinburgh and published in the leading scientific journal Nature found that high levels of TYK2 have been associated with severe COVID-19.
Through laboratory experiments using dish cultured human cells, NTU scientists found that ASO-1 effectively reduced TYK2 levels over a long period and suppressed immune signaling pathways that have been associated with autoimmune disorders.
The team led by Professor Van Anh Tuan of NTU Singapore’s College of Physical and Mathematical Sciences (SPMS) said this indicates the potential of the ASO-1 compound that forms the basis for treating autoimmune diseases.
Professor Fan, who is also the interim director of the NTU Institute of Skeletal Biology, said: “Human genetic studies have suggested that deactivation of TYK2 could provide protection against a wide range of autoimmune diseases such as rheumatoid arthritis, psoriasis, lupus and type I.
Dr Lim Kah Wai, senior research fellow at NTU and co-lead author of the study added: “With the UK-led study of critically ill COVID-19 patients, published in the journal Nature, it links high TYK2 expression to severe COVID-19, ASO- 1 It may be a therapeutic agent that deserves further research. We are planning to undertake further preclinical work to verify its therapeutic potential. ”
The results were published in February in the scientific journal Immunological prospects, A publication of the American Society of Immunologists, and the research team has filed a patent for the compound they designed.
Targeting the genetic material that leads to TYK2 production
A number of drugs that reduce inflammation due to an overactive immune response target the Janus kinase (JAK) family of four proteins: JAK1, JAK2, JAK3, and TYK2.
Recently, TYK2 has emerged as a favorite target of researchers. Since the four organ structures are so similar, it is important to selectively target TYK2 to reduce unwanted side effects.
The ASO-1 compound designed by the NTU research team is the anti-allergic oligonucleotide (ASO). ASOs are a type of RNA treatment – they target messenger RNA (mRNA), which carries the genetic instructions that cells read to make proteins. ASO-1 is designed to bind to TYK2 mRNA, thus preventing cells from producing the TYK2 protein.
The research team conducted laboratory experiments on human cell cultures and found that ASO-1 is highly effective and selective for TYK2, without any effect on other JAK proteins. Dr Lim noted that this high potency of ASO-1 competitors rivals that of recent candidate drugs that have either submitted to clinical trials or have been approved for clinical use.
The NTU team discovered an ASO-1 of over 200 potentially effective ASOs, which were engineered based on their internal expertise with nucleic acids.
The team has created an integrated platform that includes the design, synthesis, and cellular testing of RNA treatments. TYK2 stands among the group of therapeutic goals for immunology and cancer treatment, and is the primary focus of the team.
NTU researchers plan to partner with several academic collaborators to test ASO-1 in animal models and are open to industry collaboration in developing the ASO-1 compound toward clinical use.
Note to editors:
Paper “ Selective and Effective Knockdown of Tyrosine Kinase 2 by Antisense Oligonucleotides ” published in Immunological prospectsFeb 2021, 5: 70-80.
Fu Ji Ying
Director of the Corporate Communication Office
Nanyang Technological University
email: [email protected]
About Nanyang Technological University, Singapore
Nanyang Technological University of Singapore (NTU Singapore), a research-intensive public university, has 33,000 undergraduate and graduate students in engineering, business, science, humanities, arts, social sciences, and graduate schools. It also has a medical school, Lee Kong Chian College of Medicine, which was jointly established with Imperial College London.
NTU is also home to world-class independent institutes – the National Institute of Education, S Rajaratnam School of International Studies, Singapore Earth Observatory, Singapore Center for Environmental Life Sciences Engineering – and several leading research centers such as the Nanyang Environment & Water Research Institute (NEWRI) and Energy Research Institute. @ NTU ([email protected]).
NTU has been ranked among the best universities in the world by QS, and it has also been ranked as the best young university in the world for the past seven years. The university’s main campus is often listed in the top 15 campuses in the world and has 57 Green Mark (LEED equivalent) buildings, of which 95% are Green Mark Platinum accredited. Aside from the main campus, NTU also has campuses in Novena, Singapore’s healthcare district.
Under the vision of NTU Smart Campus, the university harnesses the power of digital technology and technology-enabled solutions to support better learning and living experiences, new knowledge discovery, and resource sustainability.
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