The potential of epigenetic therapy to treat disease
Epigenetic modulators are compounds in the body that operate within the nucleus of the cell to regulate or influence the expression of multiple genes, but without changing the DNA sequence of the genome. When the epigenome becomes “dysregulated,” cellular functioning is compromised or altered, leading to disease. Many diseases, including acute organ injury and cancer, may benefit from therapeutics that modulate the dysregulated epigenome, such as dysregulated DNA methylation.1-4
How it works
2. Epigenetic Modulation of Gene Expression
DNMTs are one such modulator that add methyl groups to certain regions of DNA
3. Larsucosterol Inhibits DNMTs
By binding to and inhibiting DNMTs (1, 3a, & 3b), larsucosterol reduces DNA hypermethylation, thereby modulating important cell signaling pathways
Image Source: Wang Y et al, Journal of Lipid Research. 2021; 62: 100063
Broad therapeutic potential
- Larsucosterol has demonstrated promising safety and efficacy signals in a Phase 2a clinical trial in AH7 and positive data in a Phase 1b trial in NASH.8 A Phase 2b trial in AH patients (AHFIRM) is currently underway.
- Promising preclinical data in other animal models suggests its potential to treat other acute organ injuries and chronic liver diseases.
Read about larsucosterol and its promising potential in the treatment of disease.
- Argemi J, Latasa MU, Atkinson SR, et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun. 2019;10(1):3126. doi:10.1038/s41467-019-11004-3
- Mazzone R, Zwergel C, Artico M, et al. The emerging role of epigenetics in human autoimmune disorders. Clin Epigenetics. 2019;11(1):34. doi:10.1186/s13148-019-0632-2
- Herman A, Occean JR, Sen P. Epigenetic dysregulation in cardiovascular aging and disease. J Cardiovasc Aging. 2021;1:10. doi:10.20517/jca.2021.16
- Zhao F. Dysregulated Epigenetic Modifications in the Pathogenesis of NAFLD-HCC. Adv Exp Med Biol. 2018;1061:79-93. doi: 10.1007/978-981-10-8684-7_7. PMID: 29956208.
- Wang Y, Lin W, Brown JE, et al. 25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes. J Lipid Res. 2021;62:100063.
- Gibney E, Nolan C. Epigenetics and gene expression. Heredity.2010; 105: 4–13. https://doi.org/10.1038/hdy.2010.54
- Hassanein T, McClain CJ, Vatsalya V, et al. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis. Am J Gastroenterol. 2023;10.14309/ajg.0000000000002275.
- Lawitz E, Hassanein T, Denham D, et al. Efficacy signals of 4-week oral DUR-928 in NASH subjects. Presented at: 2021 International Liver Conference; June 23-26, 2021; virtual. Poster no. 1198.