| Autor: |
Haressh Sajiir, Sahar Keshvari, Kuan Yau Wong, Danielle J. Borg, Frederik J. Steyn, Christian Fercher, Karin Taylor, Breten Taylor, Ross T. Barnard, Alexandra Müller, Md Moniruzzaman, Gregory Miller, Ran Wang, Amelia Fotheringham, Veronika Schreiber, Yong Hua Sheng, Janelle Louise Hancock, Dorothy Loo, Lucy Burr, Tony Huynh, Jack Lockett, Grant A. Ramm, Graeme A. Macdonald, Johannes B. Prins, Michael A. McGuckin, Sumaira Z. Hasnain |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-48317-x |
| Popis: |
Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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