RNA for treatment or prophylaxis of a liver disease
The present invention relates to an RNA suitable for treatment or prophylaxis of liver diseases. In particular, the present invention provides an RNA encoding at least one peptide or protein selected from the group consisting of an extracellular matrix protease, CCAAT/enhancer-binding protein alpha (CEBPA), TNF-related apoptosis-inducing ligand (TRAIL), Hepatocyte Growth Factor (HGF), hepatocyte nuclear factor 4 alpha (HNF4A), fibroblast growth factor 21 (FGF21), opioid growth factor receptor-like 1 (OGFRL1), Relaxin 1 (RLN1), Relaxin 2 (RLN2) and Relaxin 3 (RLN3), or a fragment or a variant of any of these peptides or proteins. The present invention concerns said RNA as well as compositions and kits comprising the RNA. Furthermore, the present invention relates to the RNA, compositions or kits as disclosed herein for use as a medicament, in particular for treatment or prophylaxis of a liver disease. The present invention also provides the use of the RNA, compositions or kits as disclosed herein for increasing the expression of said encoded protein, in particular in gene therapy.
1. A method for treatment of liver fibrosis, the method comprising administering to a patient in need thereof an effective amount of RNA comprising at least one coding sequence, wherein said RNA is formulated a lipid nanoparticle and administered by injection,
wherein the coding sequence encodes hepatocyte nuclear factor 4 alpha (HNF4A) having a polypeptide sequence at least 95% identical to SEQ ID NO: 14, and wherein the coding sequence comprises a nucleic acid sequence at least 90% identical to the RNA sequence of SEQ ID NO: 169.
2. The method of claim 1 , wherein the RNA is an mRNA, a viral RNA or a replicon RNA.
3. The method of claim 1 , wherein the RNA does not comprise a chemically modified sugar, a chemically modified backbone or a chemically modified nucleobase.
4. The method of claim 1 , wherein the RNA does not comprise a chemically modified nucleoside or nucleotide.
5. The method of claim 1 , wherein the RNA is not chemically modified.
6. The method of claim 1 , wherein the at least one coding sequence of the RNA comprises a nucleic acid sequence encoding a polypeptide of SEQ ID NO: 14.
7. The method of claim 1 , wherein the RNA is mono-, bi-, or multicistronic.
8. The method of claim 1 , wherein the RNA is an mRNA.
9. The method of claim 8 , wherein the RNA is mRNA comprising from 5′ to 3′: a 5′ Cap; a 5′ untranslated regions (UTR); the at least one coding sequence; a 3′ UTR and a Poly-A region.
10. The method of claim 8 , wherein the RNA is formulated in a lipid nanoparticle comprising a cationic lipid.
11. The method of claim 10 , wherein lipid nanoparticle comprises: a cationic lipid, an aggregation reducing agent, a non-cationic lipid and a sterol.
12. The method of claim 11 , wherein the aggregation reducing agent comprises a PEG-modified lipid.
13. The method of claim 1 , wherein the administering is by intravenous injection.
14. The method of claim 1 , wherein the method reduces the level of alanine aminotransferase (ALT) in the patient's serum.
15. The method of claim 1 , wherein the RNA comprises at least one chemically modified nucleotide.
16. The method of claim 15 , wherein the at least one chemically modified nucleotide comprises a chemically modified uridine.
17. The method of claim 15 , wherein the at least one chemically modified nucleotide comprises pseudouridine or 1-methyl-pseudouridine.