New Compound Reduces Overactive Immune Response Linked to Severe COVID-19 Infections

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. More recently, it has also been linked to severe COVID-19 infections, in which immune-system signaling proteins ramp up to dangerous levels, leading to damage to the body’s own cells.

The compound designed by the NTU research team, called ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes that play a key role in regulating the body’s immune response. A number of drugs that reduce inflammation resulting from an overactive immune response target the Janus kinase (JAK) family of four proteins: JAK1, JAK2, JAK3 and TYK2. Recently, TYK2 has emerged as researchers’ preferred target. As the structures of the four members are highly similar, it is important to selectively target TYK2 to limit unwanted side effects. A recent study found that high levels of TYK2 have been associated with severe COVID-19.

The ASO-1 compound designed by the NTU research team is an antisense oligonucleotide (ASO). ASOs are a type of RNA therapeutics – they target the messenger RNA (mRNA), which carries genetic instructions that cells ‘read’ to make proteins. ASO-1 is designed to bind to TYK2 mRNA, thus preventing cells from producing TYK2 protein.

The research team conducted lab experiments on human cell cultures and found ASO-1 to be highly potent and selective for TYK2, with no effect against the other JAK proteins. The researchers have noted that this high potency of ASO-1 rivals that of recent ASO drug candidates that have advanced to clinical trials or have been approved for clinical use. The NTU team discovered ASO-1 from over 200 potentially effective ASOs, which were designed based on their in-house expertise on nucleic acids. The team has established an integrated platform spanning the design, synthesis, and cellular testing of RNA therapeutics. TYK2 stands among a range of therapeutic targets for immunology and cancer therapy, which is the primary focus of the team.

“Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes,” said Professor Phan Anh Tuan from NTU Singapore’s School of Physical and Mathematical Sciences (SPMS) who led the study.

“With the UK-led study of critically ill COVID-19 patients published in Nature linking high TYK2 expression to severe COVID-19, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential,” added Dr Lim Kah Wai, NTU senior research fellow and co-lead author of the study.

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