Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition that has become a leading cause of liver-related morbidity and mortality. Affecting about a quarter of the global population, MASLD can progress from simple steatosis (fat accumulation in the liver) to metabolic dysfunction-associated steatohepatitis (MASH), potentially leading to cirrhosis or hepatocellular carcinoma (HCC). [1] Although Resmetirom is the first and only approved drug for MASLD, many patients do not respond to this therapy, underscoring the need for more targeted treatments. [2] Recent advancements in RNA interference (RNAi)-based therapies, aimed at reducing the expression of risk genes such as PNPLA3 and HSD17B13, have become a key focus in MASLD research and promising approaches to treatment.

Figure 1. Disease progression of metabolic dysfunction-associated steatotic liver disease (MASLD). [3]

HSD17B13 as a Key Therapeutic Target for MASLD & MASH

Pathologically, MASLD (formerly nonalcoholic fatty liver disease, NAFLD) is characterized by the abnormal accumulation of neutral lipids (such as triglycerides and cholesterol esters) in the lipid droplets of hepatocytes. 17β-Hydroxysteroid dehydrogenase 13 (HSD17B13) is a liver-enriched lipid droplet (LD)-associated protein that is selectively expressed in hepatocytes and localized only on the surface of lipid droplets. It is believed to play a crucial role in the biogenesis, growth, and degradation of hepatic lipid droplets. [4] MASH, the inflammatory form of MASLD, is closely linked to chronic liver disease.

Studies have shown that HSD17B13 expression is significantly elevated in the livers of MASLD patients compared to healthy individuals, while loss-of-function (LOF) variants are associated with a reduced risk of chronic liver disease and the progression of steatosis to steatohepatitis. [5-6] The abnormal expression of HSD17B13 may be one of the mechanisms driving chronic liver disease, especially MASH & other metabolic-associated liver diseases. RNAi therapies designed to inhibit HSD17B13 expression, using liver-targeted delivery platforms like GalNAc, are emerging as a promising strategy for treating MASLD and MASH. [7]

Figure 2. The role of HSD17B13 in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD/NAFLD). [8]

Development of RNAi Therapies Targeting HSD17B13

Multiple large-scale genome-wide clinical studies have demonstrated a robust and reproducible association between HSD17B13 gene variants and the natural progression of MASLD/MASH. [7] Both in vivo and in vitro studies suggest that inhibiting HSD17B13 expression is beneficial for the treatment of MASLD/MASH. [7-8] Although the exact mechanism of HSD17B13 is not yet fully understood, drug research targeting HSD17B13 has rapidly progressed based on genetic and preclinical studies.

Currently, RNAi drugs aimed at inhibiting HSD17B13 expression are gaining significant attention. Small nucleic acid companies such as Alnylam, Arrowhead, and Ionis have publicly disclosed their RNAi pipelines targeting HSD17B13, while major pharmaceutical companies like AstraZeneca, Regeneron, Amgen, Boehringer Ingelheim, GSK, and Pfizer are aldo actively pursuing HSD17B13-targeted therapies, including small molecules and siRNA, through partnerships or independent development. [7] Early clinical results indicate that several RNAi therapies not only successfully inhibit HSD17B13 expression with good tolerability, but also replicate some of the liver-protective effects seen in individuals with HSD17B13 loss-of-function (LOF) mutations, such as improvements in ALT enzyme levels, MASLD activity scores, and fibrosis stages. [9-10]

Figure 3. RNAi therapy ARO-HSD significantly reduces alanine aminotransferase (ALT) levels while lowering HSD17B13 expression. [9]


RNA interference drugs (RNAi), primarily consisting of small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), function by targeting the mRNA of human genes. Given the genetic differences between humans and mice, Cyagen has developed the H11-Alb-hHSD17B13 humanized mouse model (Product Code: I001192). This model is regulated by the Alb promoter and specifically expresses the human HSD17B13 gene in the liver, aiding in the acceleration of preclinical studies for RNAi therapies targeting the human HSD17B13 gene. Below are the specific details of the model.

H11-Alb-hHSD17B13 Mice Express Human HSD17B13 Gene and Protein

Validation studies have confirmed that H11-Alb-hHSD17B13 mice successfully express the human HSD17B13 gene in both the liver and duodenum, with significant expression of the human HSD17B13 gene and protein in the liver.

Figure 4. Expression of the human HSD17B13 gene and protein in H11-Alb-hHSD17B13 mice.

Conclusion

RNAi therapies, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) targeting human HSD17B13 genes and mRNA are the predominant approaches for effectively treating metabolic dysfunction-associated steatotic liver disease (MASLD) and aim to prevent metabolic dysfunction-associated steatohepatitis (MASH). The H11-Alb-hHSD17B13 humanized mouse model (Product Code: I001192) exhibits high expression of the human HSD17B13 gene and protein, serving as a valuable tool for preclinical drug studies that require precise targeting of human HSD17B13.

In addition, Cyagen has developed a variety of genetic disease models, inducible disease models, and humanized models for cardiovascular and metabolic disease research, including models targeting key genes such as INHBE, GLP-1R, LPA, and GDF15. These models can accelerate the development of targeted therapies for a range of metabolic disorders, including MASLD/MASH and obesity.

>>Explore More Metabolic and Cardiovascular Disease Models

 

References:
[1]Castillo-Núñez Y, Almeda-Valdes P, González-Gálvez G, Arechavaleta-Granell MDR. Metabolic dysfunction-associated steatotic liver disease and atherosclerosis. Curr Diab Rep. 2024 Jul;24(7):158-166.
[2]Caddeo A, Romeo S. Precision medicine and nucleotide-based therapeutics to treat MASH. Clin Mol Hepatol. 2024 Aug 5.
[3]Rao G, Peng X, Li X, An K, He H, Fu X, Li S, An Z. Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic. Front Med (Lausanne). 2023 Nov 27;10:1294267.
[4]Zhang HB, Su W, Xu H, Zhang XY, Guan YF. HSD17B13: A Potential Therapeutic Target for NAFLD. Front Mol Biosci. 2022 Jan 7;8:824776.
[5]Su W, Wang Y, Jia X, Wu W, Li L, Tian X, Li S, Wang C, Xu H, Cao J, Han Q, Xu S, Chen Y, Zhong Y, Zhang X, Liu P, Gustafsson JÅ, Guan Y. Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11437-42.
[6]Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018 Mar 22;378(12):1096-1106.
[7]Zhang X, Yu W, Li Y, Wang A, Cao H, Fu Y. Drug development advances in human genetics-based targets. MedComm (2020). 2024 Feb 9;5(2):e48
[8]1.Wang MX, Peng ZG. 17β-hydroxysteroid dehydrogenases in the progression of nonalcoholic fatty liver disease. Pharmacol Ther. 2023 Jun;246:108428.
[9]Mak LY, Gane E, Schwabe C, Yoon KT, Heo J, Scott R, Lee JH, Lee JI, Kweon YO, Weltman M, Harrison SA, Neuschwander-Tetri BA, Cusi K, Loomba R, Given BD, Christianson DR, Garcia-Medel E, Yi M, Hamilton J, Yuen MF. A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis. J Hepatol. 2023 Apr;78(4):684-692.
[10]Sanyal, A. J., Taubel, J., Badri, P., Bond, S., Makarova, N., Zhao, W., … Gansner, J. M. (2023). Phase 1 Study of the RNA Interference Therapeutic ALN-HSD in Healthy Adults and Patients with Nonalcoholic Steatohepatitis. Alnylam. Retrieved from: https://capella.alnylam.com/wp-content/uploads/2023/06/ALN-HSD-Phase-1_EASL-2023_FINAL.pdf

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