Hepatocyte nuclear factor four alpha antisense RNA 1 targeting polynucleotide and method of use and treatment thereof
HNF4A antisense RNA 1 targeting polynucleotides offer a targeted therapeutic strategy to modulate HNF4A expression, enhancing treatment efficacy for liver diseases like Crohn's disease and metabolic syndrome by targeting the underlying genetic and molecular mechanisms.
Patent Information
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- GENECO PTY LTD
- Filing Date
- 2025-01-29
- Publication Date
- 2026-07-23
AI Technical Summary
Current treatments for liver diseases such as Crohn's disease and metabolic syndrome lack effective therapeutic targets that address the underlying genetic and molecular mechanisms, particularly involving hepatocyte nuclear factor 4 alpha (HNF4A) polymorphisms, leading to inadequate therapeutic responses.
Development of hepatocyte nuclear factor 4 alpha (HNF4A) antisense RNA 1 targeting polynucleotides to modulate HNF4A expression, thereby addressing the underlying genetic and molecular mechanisms contributing to these diseases.
The HNF4A antisense RNA 1 targeting polynucleotides provide a targeted therapeutic approach that modulates HNF4A expression, potentially improving treatment outcomes for liver diseases by addressing the genetic and molecular pathways implicated in Crohn's disease and metabolic syndrome.
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Abstract
Description
14. Marcil, V., Sinnett, D., Seidman, E., Boudreau, F., Gendron, F.P., Beaulieu, J.F., Menard, D., Lambert, M., Bitton, A., Sanchez, R., Amre, D., et al. (2012). Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease. Genes Immun 13, 556-565. 10.1038 / gene.2012.37. 15. Dubois, V., Gheeraert, C., Vankrunkelsven, W., Dubois-Chevalier, J., Dehondt, H., Bobowski-Gerard, M., Vinod, M., Zummo, F.P., Guiza, E, Ploton, M., Dorchies, E., et al. (2020). Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver. Mol Syst Biol 16, e9156. 10.15252 / msb.20199156. 16. Marcil, V., Amre, D., Seidman, E.G., Boudreau, F., Gendron, F.P., Menard, D., Beaulieu, J.F., Sinnett, D., Lambert, M., and Levy, E. (2015). Hepatocyte nuclear 5 factor 4 alpha polymorphisms and the metabolic syndrome in French-Canadian youth. PLoS One 10, e0117238. 10.1371 / journal.pone.0117238. 17. Babeu, J.P., and Boudreau, F. (2014). Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World J Gastroenterol 20, 22-30. 10.3748 / wjg. v20.il.22. 10 18. Liu, L., Yannam, G.R., Nishikawa, T., Yamamoto, T., Basma, H., Ito, R., Nagaya, M., Dutta-Moscato, J., Stolz, D.B., Duan, F., Kaestner, K.H., et al. (2012). The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis. Hepatology 55, 1529-1539. 10.1002 / hep.24815. [000209]
Claims
1. A pharmaceutical composition comprising one or more hepatocyte nuclear factor four alpha antisense RNA 1 (HNF4A-AS1) targeting polynucleotides, wherein the one or more HNF4A-AS1 targeting polynucleotides is capable of repressing HNF4A-AS1 in a subject resulting in upregulation of HNF4A expression and / or increasing HNF4A Pl :P2 isoform ratio in the subject.
2. The pharmaceutical composition of claim 1, wherein the nucleotide sequence of each of the one or more HNF4A-AS1 targeting polynucleotides is at least about 80%, about 85%, about 90%, about 95% or about 100% identical to the nucleotide sequence of SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 35,or a combination thereof.
3. The pharmaceutical composition of claim 1, wherein the one or more HNF4A-AS1 targeting polynucleotides comprise a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a microRNA (miRNA), a ribozyme, a deoxyribozyme, an aptamer, or a combination thereof.
4. The pharmaceutical composition of claim 1, wherein the nucleotide sequence of the one or more HNF4A-AS1 targeting polynucleotides is at least about 80%, about 85%, about 90%, about 95% or about 100% identical to the nucleotide sequence of SEQ ID NO. 31 or SEQ ID NO. 32.
5. The pharmaceutical composition of claim 4, wherein the HNF4A-AS1 comprises HNF4A-ASla, HNF4A-ASlb, or a combination thereof.
6. The pharmaceutical composition of claim 1 further comprising a nanoparticle wherein the nanoparticle encapsulates the one or more HNF4A-AS1 targeting polynucleotides.
7. The pharmaceutical composition of claim 6, wherein the nanoparticle comprises lipid nanoparticle, polymer nanoparticle, lipid-polymer hybrid nanoparticle, liposome, exosome, virus or virus-like particle.
8. The pharmaceutical composition of claim 7, further comprising a fusion protein and a packaging domain wherein the nanoparticle comprises exosome, wherein the one or more HNF4A-AS 1 targeting polynucleotides is fused to the packaging domain, wherein the fusion protein comprises an exosome-associated transmembrane protein fused to a packaging protein, wherein the packaging domain comprises an UR domain, a L2 domain, or a combination thereof and wherein the packaging domain is capable ofbinding with the packaging protein.
9. The pharmaceutical composition of claim 6, wherein the one or more HNF4A-AS1 targeting polynucleotides is further fused to a nuclear localization sequence SIRLOIN.
10. The pharmaceutical composition of claim 8, wherein the fusion protein comprises CD63-Ula, CD81-Ula, PTGFRN-Ula, or a combination thereof.
11. The pharmaceutical composition of claim 7, wherein the exosome further comprises an Ago2 protein or a S387A mutant thereof.
12. The pharmaceutical composition of claim 7, wherein the exosome further comprises a modified myoferlin protein.
13. The pharmaceutical composition of claim 12, wherein the modified myoferlin protein comprises C2F, C2G, transmembrane domain of the myoferlin protein, or a combination thereof.
14. The pharmaceutical composition of claim 12, wherein the modified myoferlin protein further comprises a connexin 43 protein or a S3 68A mutant thereof.
15. The pharmaceutical composition of claim 8, wherein the exosome is prepared using an exosome-based packaging and delivery system comprising one or more cargo RNA encoding plasmid encoding the one or more HNF4A-AS 1 targeting polynucleotides of claim 1 fused to the packaging domain, and one or more fusion protein encoding plasmids encoding the fusion protein comprising an exosome-associated transmembrane protein fused to a packaging protein.
16. The pharmaceutical composition of claim 15, wherein the exosome-based delivery and packaging system further comprises a plasmid encoding a modified myoferlin protein, a connexin 43 protein or a S368A mutant thereof, or a combination thereof.
17. A method of treatment of a HNF4A-associated disease in a subject comprising the step of administering a therapeutically effective amount of the pharmaceutical composition of claims 1 to the subject.
18. The method of claim 17, wherein the HNF4A-associated disease comprises hepatocellular cancer, fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), cirrhosis of the liver, accumulation of fat in the liver, inflammation of the liver, hepatocellular necrosis, liver fibrosis, and nonalcoholic fatty liver disease (NAFLD), liver failure of any cause, polycystic kidney disease, inflammatory bowel disease (IBD), and maturity onset diabetes of the young (MODY).
19. A method of downregulating HNF4A P2 isoform expression in a subject comprising the step of repressing HNF4A-AS1 in the subject.
20. The method of claim 19, wherein the method increases the HNF4A P1:P2 isoform expression ratio in a subject.
21. The method of claim 19, wherein the method increases the HNF4A P1:P2 isoform expression ratio of at least a pair of Pl and P2 isoform in a subject.
22. The method of claim 19, wherein the subject is diagnosed with a HNF4A-associated disease.
23. The method of claim 22, wherein the HNF4A-associated disease comprises hepatocellular cancer, fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), cirrhosis of the liver, accumulation of fat in the liver, inflammation of the liver, hepatocellular necrosis, liver fibrosis, nonalcoholic fatty liver disease (NAFLD), liver failure of any cause, polycystic kidney disease, inflammatory bowel disease (IBD), and maturity onset diabetes of the young (MODY).
24. The method of claim 19, wherein the step of repressing HNF4A-AS1 is performed by administration of HNF4A-AS1 targeting polynucleotides capable of repressing HNF4A-AS 1 via RNA interference wherein the HNF4A-AS 1 targeting polynucleotides comprises a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a microRNA (miRNA), a ribozyme, a deoxyribozyme, an aptamer, or a combination thereof.
25. The method of claim 19, the step of repressing HNF4A-AS1 in the subject is performed by administration of the pharmaceutical composition of claim 1 to the subject.