A Korean research team has discovered a new mechanism for alleviating chronic inflammation, such as rheumatoid arthritis, by controlling gene switches.
A research team led by Professor Kim Lark-kyun and Drs. Kim Soo-min and Cho Min-jung of the Department of Biomedical Sciences at Yonsei University College of Medicine, in collaboration with Professor Richard Flavell's research team at Yale School of Medicine in the U.S., announced on Tuesday that they have successfully inhibited the expression of the inflammatory protein “Tumor Necrosis Factor alpha (TNFα)” by targeting the “super-enhancer,” a genetic regulatory mechanism in immune cells.
Chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and sepsis, worsen as immune cells become overly activated, leading to excessive secretion of the inflammatory protein TNFα. Treatment typically involves using antibody therapies that block the production of this protein. However, these are expensive, ineffective for some patients, and carry risks such as infection.
The research team focused on super-enhancers and their transcription products, eRNAs. Super-enhancers and eRNAs act as molecular switches that regulate specific gene expression, and their ability to activate only during disease states makes them promising targets for selective therapy.
The team identified TNF-9 super enhancer, a key gene switch regulating TNFα, in mouse immune cells.
Using advanced genomic analysis technology, they identified 62 super-enhancers that regulate gene activation by producing endogenous RNA (eRNA). Among these, TNF-9 eRNA, the core super-enhancer of TNFα, was selected as the primary target. When TNF-9 eRNA was removed or its production was inhibited, TNFα levels decreased, and symptoms of arthritis and psoriasis were alleviated.
The same results were observed in experiments using patient-derived cells. The research team confirmed that the DHS44500 super-enhancer, corresponding to TNF-9 in mice, was activated in immune cells from patients with rheumatoid arthritis. When DHS44500 eRNA was inhibited in patient blood immune cells using ASO (antisense oligonucleotide), TNFα expression significantly decreased, and inflammatory responses were also alleviated.
The ASO used in this study is a next-generation therapeutic platform that regulates the expression of specific RNA. Spinraza, a treatment for spinal muscular atrophy, is a representative ASO-based new drug.
In this study, it was confirmed that precisely inhibiting TNF-α eRNA, which is specifically activated by inflammation, using ASO, can selectively block pathological inflammation while preserving normal immune function.
“This study is the first case of directly targeting super-enhancer-derived eRNA with ASO to precisely inhibit TNFα expression,” Professor Kim said. “Existing antibody therapies indiscriminately block the entire TNFα protein, posing a risk of infection. We hope this study will lay the foundation for the development of next-generation chronic inflammation therapies that reduce side effects while enhancing therapeutic efficacy.”
This study was published in the latest issue of the international academic journal Advanced Science under the title “Targeting eRNA-Producing Super-Enhancers Regulates TNFα Expression and Mitigates Chronic Inflammation in Mice and Patient-Derived Immune Cells.”