Researchers from Nanyang Technological University (NTU), Singapore, have discovered a compound that is capable of dampening immune overactivity without the cost of reducing the immune response.
The new compound, ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes involved in immune response regulation. These enzymes have received attention in recent years as targets for drugs to treat immune system overactivity, and TYK2 is a possible therapeutic target for cancer treatment. A recent study found that high levels of TYK2 have been associated with severe COVID.
“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 Phan Anh, Professor and Interim Director, Institute of Structural Biology, NTU.
Co-lead author Dr Lim Kah Wai, NTU senior researcher, added: “With the UK-led study of critically ill COVID patients published in Nature linking high TYK2 expression to severe COVID, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential.”
The ASO-1 compound designed by the researchers is an antisense oligonucleotide (ASO), which targets messenger RNA (mRNA). ASO-1 was identified from over 200 potentially effective ASOs designed by the team. ASO-1 is designed to bind to TYK2 mRNA and prevent the cells from making the TYK2 protein. ASO-1 has to be highly selective for TYK in order to prevent side effects involving other JAK enzymes.
Through in vitro testing, the NTU scientists found that ASO-1 greatly reduced TYK2 levels over a sustained period and inhibited immune signalling pathways associated with autoimmune disorders. This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, There was also no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates under development.
The team plans academic collaboration for further development of ASO-1 and animal model testing.
Source: News-Medical.Net
