WO2024263031A1 - Means and methods for alleviating symptoms associated with bile acid-related liver disease. - Google Patents

Abstract

The invention provides an inhibitor of bile acid conjugation and/or reconjugation, for use in a method of alleviating symptoms and decreasing organ damage in a subject suffering from a condition characterized by the accumulation of bile acids, such as cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH), Exemplary inhibitors suppress or inhibit the expression or activity of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or its gene product, or the solute carrier family 27 member 5 (SLC27A5) gene or its gene product.

Description

P134879PC00 Title: Means and methods for alleviating symptoms associated with bile acid-related liver disease. The invention relates to the field of medicine and pharmacology. More in particular, it relates to novel means and methods for alleviating symptoms and decreasing organ damage in conditions characterized or complicated by the accumulation of bile acids and hepatocellular injury with inflammation, such as cholestatic liver diseases and non-alcoholic steatohepatitis (NASH) and/or improving or prolonging native liver survival in a patient suffering from such condition. Cholestatic liver diseases (CLDs), i.e., diseases associated with impaired production of bile by the liver, lead to the hepatic accumulation of bile acids and other toxic molecules, inducing liver damage and deteriorating liver function. CLD is a continuous process of inflammation, cellular destruction, and regeneration of liver parenchyma, which leads to fibrosis and cirrhosis. Most of the CLDs have a progressive course, leading to development of severe liver damage, leaving liver transplantation the only option for survival. CLDs may have widely varying etiologies, in a number of cases with still unresolved underlying causes. Biliary atresia and different forms of syndromic or non-syndromic paucity of bile ducts become apparent in neonatal life. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) may arise at adult age and are related to autoimmunity, while a third group, such as the group of progressive familial intrahepatic cholestasis (PFIC), are autosomal recessive disorders in which mutations in a single gene cause the disease. However, the common denominator in these diseases is that the systemic and intrahepatic accumulation of bile acids play a major role in the progressive deterioration of liver function. PFIC refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Multiple types of PFIC have been identified of which the first three subtypes are related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 (defect in ATP8B1) and PFIC2 (defect in ABCB11 aka BSEP) usually appear in the first months of life, whereas onset of PFIC3 (defect in ABCB4 aka MDR3) may also occur later in infancy, in childhood or even during adulthood. More recently defined mutations in TJP2, FXR and MYO5B underlie PFIC 4, 5 and 6, respectively. Furthermore, recently a number of other genes has been identified that may represent putative new PFIC genes. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. For example, 70% of PFIC2 patients (who have a loss-of-function mutation in the gene encoding the bile salt export pump encoded by ABCB11) need a liver transplantation before the age of 18 years. Furthermore, due to the absence or very low concentrations of bile acids in the intestine, patients often suffer from fat-soluble vitamin deficiencies. The deterioration of liver function is, however, the most severe problem in these patients as this aspect can currently not be successfully treated. Patients with CLD are currently frequently treated with the hydrophilic bile acid ursodeoxycholic acid (UDCA), which is only effective in part of the patients with certain types of CLDs (like in ±40% of patients with PBC), but not effective in many other types. Obeticholic acid (OCA) is approved for the treatment of PBC in patients with an incomplete response to UDCA or in those that are intolerant to UDCA. Still, substantial amounts of PBC patients do not respond to treatment and pruritus is a frequently observed adverse effect. In addition, inhibition of the ileal bile acid uptake transporter (ASBT; IBAT) has recently been demonstrated to be effective in part of the patients that are still able to secrete (some) bile acids into the bile (Nomden et al., Gastroenterology, 2023 Mar 31;S0016-5085(23) and Thompson et al., Lancet Gastroenterol Hepatol.2022 Sep;7(9):830-842.). WO2014/144650 A1 relates to a method for treating or ameliorating PSC and inflammatory bowel disease (PSC-IBD) in an individual comprising non-systemically administering to the individual a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. A detailed description of the current state-of-the-art of treatment strategies for CLDs is found in Nevens et al. (J. of Hepatology, February 2023. vol.78 j 430–441). Non-alcoholic steatohepatitis (NASH), nowadays also referred to as metabolic dysfunction associated fatty liver disease (MASH), occurs when the fat buildup in the liver leads to inflammation (hepatitis) and scarring. As used herein, the terms ‘’NASH’’ and MASH” refer to the same disease condition and are used interchangeably. MASH is defined as 5% or greater hepatic steatosis with hepatocellular injury and inflammation, with or without fibrosis. In contrast, nonalcoholic fatty liver disease (NAFLD), is defined as 5% or greater hepatic steatosis without evidence of hepatocellular injury or fibrosis. After years of damage due to fibrosis, MASH can lead to cirrhosis, which is severe scarring of the liver that can lead to further complications such as loss of liver function, liver failure and liver cancer. In 2024, the U.S. Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non- alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. However, clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Overall, it can be concluded that there is an unmet need to enlarge the number of therapeutic options for this class of severe and disabling diseases. In search for novel approaches to delay or even reverse the development of organ damage and resultant deterioration of liver function in CLD patients, the present inventors used CRISPR/Cas9-mediated hepatocyte-specific genome editing in novel mouse models with a human-like bile acid metabolism that display features of human CLDs. It was surprisingly found that inhibition of bile acid conjugation results in a reduction of liver damage in female Cyp2c70^-/- mice displaying a phenotype that resembles human PBC and PSC as well as in Cyp2c70/Abcb4-double knockout mice, which is a new murine model for the inheritable human cholestatic disease PFIC3. The quantitatively major solutes in human and murine bile are N- acyl conjugates of cholanoates (C24 bile acids) with glycine or taurine. These bile acid-amino acid conjugates are actively secreted into bile by ABCB11/BSEP to promote the generation of bile flow and to serve as detergents in the gastrointestinal tract to aid the absorption of dietary fats and fat-soluble vitamins. Newly synthesized bile acids already acquire acyl- CoA during intermediate steps in the bile acid synthesis pathway and are conjugated to either glycine or taurine by bile acid-CoA:amino acid N- acyltransferase (BAAT). Bile acids that return to the liver in unconjugated form during their enterohepatic circulation, i.e., after microbial deconjugation in the intestine, require activity of bile acid CoA synthase SLC27A5, aka FATP5 (EC 6.2.1.7), prior to interaction with BAAT and resecretion into bile as a conjugated bile acid. Importantly, preclinical data are herein provided which indicate that inhibition of bile acid conjugation reduces organ (liver) damage in mice. Conceivably, this is achieved by the fact that unconjugated bile acids can diffuse over cell membranes and thus will not become ‘trapped’ inside the hepatocytes like conjugated bile acids are. Furthermore, unconjugated bile acids expelled at the canalicular domain of the hepatocytic plasma membrane stimulate bile flow substantially (based on recently obtained murine data), thereby diluting the bile, and thus reducing its toxicity, and preserve biliary excretion of other potentially toxic metabolites. Additionally, unconjugated bile acids expelled at the basolateral membrane may enter the systemic blood circulation and leave the body via urine. Herewith, the invention provides a novel approach to alleviate symptoms associated with a bile acid-related liver disease that is accompanied by hepatocellular injury and inflammation. For example, it can reduce the development of liver damage in patients with cholestatic liver diseases and alleviate severe symptoms associated with impaired liver function such as pruritus. Notably, the inhibition of bile acid conjugation, for instance by inhibiting the bile acid conjugation enzyme BAAT and/or bile acid CoA synthase SLC27A5, may preserve liver function in CLD patients, delaying or preventing the need for a liver transplantation in these patients. Accordingly, the invention relates to an inhibitor of bile acid conjugation and/or reconjugation, for use as a medicament. In one embodiment, the invention provides an inhibitor of bile acid conjugation and/or reconjugation, for use in a method of alleviating symptoms in a subject suffering from a cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH), wherein the inhibitor suppresses or inhibits the expression or activity of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or the solute carrier family 27 member 5 (SLC27A5) or its gene product. Also provided is an inhibitor of bile acid conjugation and/or reconjugation, for use in a method of treating a cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH; MASH) in a subject, wherein the inhibitor suppresses or inhibits the expression or activity of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or the solute carrier family 27 member 5 (SLC27A5) or its gene product. Further aspects relate to is an inhibitor of bile acid conjugation and/or reconjugation, for use in a method for alleviating symptoms and/or decreasing organ damage, e.g. liver damage, in a subject suffering from a condition characterized or complicated by the accumulation of (systemic and/or intrahepatic) bile acids. Some embodiments relate to an inhibitor of bile acid conjugation and/or reconjugation, for use in a method of alleviating symptoms associated with a bile acid-related liver disease, in particular a bile acid-related liver disease having an inflammatory aspect, and/or for improving or prolonging native liver survival in a subject suffering from bile acid-related liver disease such as CLD. In one embodiment, the inhibitor targets the expression or activity of human bile acid-CoA:amino acid N-acyltransferase (BAAT) gene, or the gene product hereof. In another embodiment, the inhibitor targets the expression or activity of the human Solute carrier family 27 member 5 (SLC27A5) gene, or a the gene product thereof. Also envisaged is the combined targeting of BAAT and SLC27A5. In some embodiments, the invention provides an inhibitor that inhibits bile acid conjugation and/or reconjugation by targeting the expression or activity of the BAAT gene, the SLC27A5 gene, or its gene product, for use in a method of treating a cholestatic liver disease (CLD) or NASH (MASH), or a related condition characterized by the accumulation of bile acids and hepatocellular injury and inflammation. The present concept of inhibiting bile acid conjugation (by inhibiting BAAT and/or SLC27A5 activity or expression) has never been suggested in the art as a viable therapeutic approach, let alone in the treatment strategy for CLDs. CN113813340A relates to a naturally occurring dendrobium alkaloid and its therapeutic application in cholestasis. Effects of the alkaloid compound in a DDC mouse model include a reduction of liver tissue lesions and increased serum ALT, AST and TBIL levels. CN113813340A shows (see Fig.4) that BAAT (and Fxr) mRNA expression is decreased in the DDC-treated mice, whereas treatment with dendrobium alkaloids showed an up-regulation trend. Hence, CN113813340A teaches away from using an inhibitor of BAAT with the purpose of treating a CLD according to the present invention. WO2005/019423 relates to a transgenic Fatty Acid Transport Protein 5 (FATP5) non-human knockout mammal and to methods for the identification of agents, e.g., therapeutic agents, that inhibit FATP5 activity. WO2005/019423 merely hypothesizes, yet fails to provide an enabling disclosure of methods of treating diseases or conditions associated with FATP5 function, e.g., obesity, insulin resistance, type 2 diabetes, dyslipidemia, fatty liver disease, and cardiovascular disease. Importantly, while WO2005/019423 alleges that FATP5 inhibition is beneficial for fatty liver disease (steatosis), which is a simple steatosis i.e. fat accumulation in the liver without hepatocellular injury and inflammation, contrary to what is encountered in CLD and NASH (MASH). Lin et al. (Biomed Pharmacother.2022 Jun:150:112984) report on an FXR agonist (OCA; obeticholic acid) which would allegedly inhibit human FATP5 activity in transfected HEK293 cells. The authors speculate that an hFATP5 inhibitor might be a promising drug candidate for NAFLD. However, OCA has been evaluated for NAFLD in clinical trials but did not reach predefined endpoints. Furthermore, NAFLD patients do not have an impaired bile formation, i.e., NAFLD patients are not cholestatic. Therefore, the study by Lin et al. fails to teach or suggest an inhibitor of FATP5/SLC27A5 for use in a method of alleviating symptoms in a subject suffering from CLD or NASH. Gerussi et al. (Ann. Hepatol.2020 Jan-Feb;19(1):5-16) provide a review on therapies for rare CLDs. It discloses inter alia norUDCA for ameliorating primary sclerosing cholangitis in mice. norUDCA is a synthetic bile acid molecule that is not naturally found in mammals, which cannot be conjugated by the hepatic bile acid conjugating machinery due to its shortened side-chain. It does not inhibit the conjugation of endogenous bile acids e.g. by targeting BAAT or SLC27A5 and relies on a completely different mode of action. Where existing therapies aim to make the bile acid pool more hydrophilic (e.g., with UDCA) or to exploit residual activity of the bile acid transporter BSEP (e.g., using chaperones), the current approach de facto encompasses changing a severe cholestatic disease into a different yet much less severe disease: i.e., one with a much more benign phenotype; limited liver damage, clinical symptoms are mostly related to impaired absorption of fat-soluble vitamins (Setchell et al. Gastroenterology, 2013 May;144(5):945-955.e6), which can be treated or at least managed to an acceptable level. Hence, the success of the present approach could not have been predicted in view of the prior art. The invention also provides an inhibitor of BAAT, an inhibitor of SLC27A5, or the combination thereof (i.e., inhibitors of both BAAT and SLC27A5 as targets) as medicament or therapeutic agent(s). BAAT (also known as BACAT; BACD1; BAT; HCHO; NCBI Gene ID: 570) encodes an enzyme (EC 2.3.1.65) that catalyzes the addition of glycine or taurine to C24 bile acids in hepatocytes. This conjugation enhances aqueous solubility at the pH of the proximal intestine where the conjugated bile acids enter the intestinal lumen. This increases the intraluminal bile acid concentrations available for solubilization and subsequent absorption of lipids, i.e., (saturated) fatty acids, cholesterol and fat-soluble vitamins (summary by Setchell et al., 2013). Hence, patients with BAAT deficiency display fat-soluble vitamin deficiencies, which can be addressed by supplementation and/or treatment with UDCA or GDCA. However, in case of partial inhibition of bile acid (re)conjugation fat-soluble vitamin deficiencies are unlikely to occur. The amino acid sequence of the human BAAT protein (GenBank: CAG46716.1); is MIQLTATPVSALVDEPVHIRATGLIPFQMVSFQASLEDENGDMFYSQAH YRANEFGEVDLNHASSLGGDYMGVHPMGLFWSLKPEKLLTRLLKRDV MNRPFQVQVKLYDLELIVNNKVASAPKASLTLERWYVAPGVTRIKVREG RLRGALFLPPGEGLFPGVIDLFGGLGGLLEFRASLLASRGFASLALAYHN YEDLPRKPEVTDLEYFEEAANFLLRHPKVFGSGVGVVSVCQGVQIGLSM AIYLKQVTATVLINGTNFPFGIPQVYHGQIHQPLPHSAQLISTNALGLLEL YRTFETTQVGASQYLFPIEEAQGQFLFIVGEGDKTINSKAHAEQAIGQLK RHGKNNWTLLSYPGAGHLIEPPYSPLCCASTTHDLRLHWGGEVIPHAAA QEHAWKEIQRFLRKHLIPDVTSQL (SEQ NR: 1) It is encoded by the nucleic acid sequence (BAAT coding sequence): ATGATCCAGTTGACAGCTACCCCTGTGAGTGCACTTGTTGATGAGC CAGTGCATATCCGAGCTACAGGCCTGATTCCCTTTCAGATGGTGAGTTTTCAG GCATCACTGGAAGATGAAAACGGAGACATGTTTTATTCTCAAGCCCACTATAG GGCCAATGAATTCGGTGAGGTGGACCTGAATCATGCTTCTTCACTTGGAGGGG ATTATATGGGAGTCCACCCCATGGGTCTCTTCTGGTCTCTGAAACCTGAAAAG CTATTAACAAGACTGTTGAAAAGAGATGTGATGAATAGGCCTTTCCAGGTCCA AGTAAAACTTTATGACTTAGAGTTAATAGTGAACAATAAAGTTGCCAGTGCTC CAAAGGCCAGCCTGACTTTGGAGAGGTGGTATGTGGCACCTGGTGTCACACG AATTAAGGTTCGAGAAGGCCGCCTTCGAGGAGCTCTCTTTCTCCCTCCAGGAG AGGGTCTCTTCCCAGGGGTAATTGATTTGTTTGGTGGTTTGGGTGGGCTGCTT GAATTTCGGGCCAGCCTCCTAGCCAGTCGTGGCTTCGCCTCCTTGGCCTTGGC TTACCATAACTATGAAGACCTGCCCCGCAAACCAGAAGTAACAGATTTGGAAT ATTTTGAGGAGGCTGCCAACTTTCTCCTGAGACATCCAAAGGTCTTTGGCTCA GGCGTTGGGGTAGTCTCTGTATGTCAAGGAGTACAGATTGGACTATCTATGGC TATTTACCTAAAGCAAGTCACAGCCACGGTACTTATTAATGGGACCAACTTTCC TTTTGGCATTCCACAGGTATATCATGGTCAGATCCATCAGCCCCTTCCCCATTC TGCACAATTAATATCCACCAATGCCTTGGGGTTACTAGAGCTCTATCGCACTTT TGAGACAACTCAAGTTGGGGCCAGTCAATATTTGTTTCCTATTGAAGAGGCCC AGGGGCAATTCCTCTTCATTGTAGGAGAAGGTGATAAGACTATCAACAGCAAA GCACACGCTGAACAAGCCATAGGACAGCTGAAGAGACATGGGAAGAACAACT GGACCCTGCTATCTTACCCTGGGGCAGGCCACCTGATAGAACCTCCCTATTCT CCTCTGTGCTGTGCCTCAACGACCCACGATTTGAGGTTACACTGGGGAGGAGA GGTGATCCCACACGCAGCTGCACAGGAACATGCTTGGAAGGAGATCCAGAGA TTTCTCAGGAAGCACCTCATTCCAGATGTGACCAGTCAACTCTAA (SEQ NR: 2). See also Figure 11 for mRNA coding sequences and polypeptide sequences of BAAT. Alternatively, the invention provides an inhibitor that targets (reduces, suppresses, decreases) the expression or activity of the SLC27A5 gene, or a gene product thereof, for use as a medicament. The human SLC27A5 (solute carrier family 27 member 5) gene encodes the bile acyl- CoA synthetase, an isozyme of very long-chain acyl-CoA synthetase (VLCS). This gene is also known as BAL; ACSB; BACS; FATP5; ACSVL6; FACVL3; FATP-5; VLACSR; VLCSH2; VLCS-H2 and has a mouse ortholog. In addition to activating bile acids, SLC27A5 is capable of activating very long- chain fatty-acids containing 24 or 26 carbons. It is expressed in liver and associated with the endoplasmic reticulum but not with peroxisomes. It plays an important role in the bile acid re-conjugation following recycling to the liver, in particular after the reuptake of unconjugated primary and secondary bile acids from the intestine. It mainly functions as a bile acid acyl-CoA synthetase catalyzing the activation of bile acids via ATP- dependent formation of bile acid-CoA thioesters, which is necessary for their subsequent conjugation with glycine or taurine. Both primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (e.g., deoxycholic acid and lithocholic acid) are the principal substrates (Steinberg et al. J. Biol. Chem.277:24771-24779 (2002). The amino acid sequences of the 3 known isoforms of the human SLC27A5 protein are as follows: Long-chain fatty acid transport protein 5 isoform 1 precursor [Homo sapiens], NCBI Reference Sequence: NP_036386.1: MGVRQQLALLLLLLLLLWGLGQPVWPVAVALTLRWLLGDPTCCVLLGL AMLARPWLGPWVPHGLSLAAAALALTLLPARLPPGLRWLPADVIFLAKI LHLGLKIRGCLSRQPPDTFVDAFERRARAQPGRALLVWTGPGAGSVTFG ELDARACQAAWALKAELGDPASLCAGEPTALLVLASQAVPALCMWLGL AKLGCPTAWINPHGRGMPLAHSVLSSGARVLVVDPDLRESLEEILPKLQ AENIRCFYLSHTSPTPGVGALGAALDAAPSHPVPADLRAGITWRSPALFI YTSGTTGLPKPAILTHERVLQMSKMLSLSGATADDVVYTVLPLYHVMGL VVGILGCLDLGATCVLAPKFSTSCFWDDCRQHGVTVILYVGELLRYLCNI PQQPEDRTHTVRLAMGNGLRADVWETFQQRFGPIRIWEVYGSTEGNMG LVNYVGRCGALGKMSCLLRMLSPFELVQFDMEAAEPVRDNQGFCIPVG LGEPGLLLTKVVSQQPFVGYRGPRELSERKLVRNVRQSGDVYYNTGDVL AMDREGFLYFRDRLGDTFRWKGENVSTHEVEGVLSQVDFLQQVNVYGV CVPGCEGKVGMAAVQLAPGQTFDGEKLYQHVRAWLPAYATPHFIRIQD AMEVTSTFKLMKTRLVREGFNVGIVVDPLFVLDNRAQSFRPLTAEMYQA VCEGTWRL (SEQ NR: 4) Long-chain fatty acid transport protein 5 isoform 2 precursor [Homo sapiens], NCBI Reference Sequence: NP_001308125.1: MGVRQQLALLLLLLLLLWGLGQPVWPVAVALTLRWLLGDPTCCVLLGL AMLARPWLGPWVPHGLSLAAAALALTLLPARLPPGLRWLPADVIFLAKI LHLGLKIRGCLSRQPPDTFVDAFERRARAQPGRALLVWTGPGAGSVTFD LRESLEEILPKLQAENIRCFYLSHTSPTPGVGALGAALDAAPSHPVPADL RAGITWRSPALFIYTSGTTGLPKPAILTHERVLQMSKMLSLSGATADDVV YTVLPLYHVMGLVVGILGCLDLGATCVLAPKFSTSCFWDDCRQHGVTVI LYVGELLRYLCNIPQQPEDRTHTVRLAMGNGLRADVWETFQQRFGPIRI WEVYGSTEGNMGLVNYVGRCGALGKMSCLLRMLSPFELVQFDMEAAE PVRDNQGFCIPVGLGEPGLLLTKVVSQQPFVGYRGPRELSERKLVRNVR QSGDVYYNTGDVLAMDREGFLYFRDRLGDTFRWKGENVSTHEVEGVLS QVDFLQQVNVYGVCVPGCEGKVGMAAVQLAPGQTFDGEKLYQHVRAW LPAYATPHFIRIQDAMEVTSTFKLMKTRLVREGFNVGIVVDPLFVLDNRA QSFRPLTAEMYQAVCEGTWRL (SEQ NR: 5) Long-chain fatty acid transport protein 5 isoform 3 precursor [Homo sapiens], Ensemble Reference: ENST00000594786.1 SLC27A5-204: MAAVQLAPGQTFDGEKLYQHVRAWLPAYATPHFIRIQDAMEVTSTFKL MKTRLVREGFNV GIVVDPLFVLDNRAQSFRPLTAEMYQAVCEGTWRL (SEQ NR: 6) The isoforms are encoded by the nucleic acid sequences listed below (only coding sequences provided): Homo sapiens solute carrier family 27 member 5 (SLC27A5), transcript variant 1, mRNA NCBI Reference Sequence: NM_012254.3 Ensemble Reference: ENST00000263093.7 SLC27A5-201 ATGGGTGTCAGGCAACAGTTGGCCTTGCTGCTGCTGCTGCTGCTCCTGCTCTG GGGCCTGGGGCAGCCAGTGTGGCCAGTCGCTGTGGCCTTGACCCTGCGCTGG CTCCTGGGGGATCCCACATGTTGCGTGCTACTTGGGCTGGCCATGTTAGCACG GCCCTGGCTCGGCCCCTGGGTGCCCCATGGGCTGAGCCTGGCAGCTGCGGCC CTGGCACTAACCCTCCTGCCAGCACGGCTGCCCCCAGGACTACGCTGGCTGCC GGCTGATGTGATCTTCTTGGCCAAGATCCTCCACCTGGGCCTGAAGATCAGGG GATGCTTGAGCCGGCAGCCGCCTGACACCTTTGTAGATGCCTTCGAGCGGCGA GCACGAGCGCAGCCTGGCAGGGCACTCTTGGTGTGGACGGGGCCTGGGGCCG GCTCAGTCACCTTTGGTGAGCTGGATGCCCGGGCCTGCCAGGCGGCATGGGC CCTGAAGGCTGAGCTGGGTGACCCTGCGAGCCTGTGTGCCGGGGAGCCTA CTGCCCTCCTTGTGCTGGCTTCCCAGGCCGTTCCAGCCCTGTGTATGTGGCTG GGGCTGGCCAAGCTGGGCTGCCCAACAGCCTGGATCAACCCGCATGGCCGGG GGATGCCCCTGGCGCACTCTGTGCTGAGCTCTGGGGCCCGGGTGCTGGTGGT GGACCCAGACCTCCGGGAGAGCCTGGAGGAGATCCTTCCCAAGCTGCAGGCT GAGAACATCCGCTGCTTCTACCTCAGCCATACCTCCCCTACACCAGGGGTGGG GGCTCTGGGGGCTGCCCTGGATGCAGCGCCCTCCCACCCAGTGCCTGCTGAC CTGCGTGCTGGGATCACATGGAGAAGCCCTGCCCTCTTCATCTATACCTCGGG GACCACTGGCCTCCCGAAGCCAGCCATCCTCACGCATGAGCGGGTACTGCAG ATGAGCAAGATGCTGTCCTTATCTGGGGCCACAGCTGATGATGTGGTTTACAC GGTCCTGCCTCTGTACCACGTGATGGGACTTGTCGTTGGGATCCTCGGCTGCT TAGATCTCGGAGCCACCTGTGTTCTGGCCCCCAAGTTCTCTACTTCCTGCTTCT GGGATGACTGTCGGCAGCATGGCGTGACAGTGATCCTGTATGTGGGCGAGCT CCTGCGGTACTTGTGTAACATTCCCCAGCAACCAGAGGACCGGACACATACAG TCCGCCTGGCAATGGGCAATGGACTACGGGCTGATGTGTGGGAGACCTTCCA GCAGCGCTTCGGTCCTATTCGGATCTGGGAAGTCTACGGCTCCACAGAAGGCA ACATGGGCTTAGTCAACTATGTGGGGCGCTGCGGGGCCCTGGGCAAGATGAG CTGCCTCCTCCGAATGCTGTCCCCCTTTGAGCTGGTGCAGTTCGACATGGAGG CGGCGGAGCCTGTGAGGGACAATCAGGGCTTCTGCATCCCTGTAGGGCTAGG GGAGCCGGGGCTGCTGCTGACCAAGGTGGTAAGCCAGCAACCCTTCGTGGGC TACCGCGGCCCCCGAGAGCTGTCGGAACGGAAGCTGGTGCGCAACGTGCGGC AATCGGGCGACGTTTACTACAACACCGGGGACGTACTGGCCATGGACCGCGA AGGCTTCCTCTACTTCCGCGACCGCCTCGGGGACACCTTCCGATGGAAGGGCG AGAACGTGTCCACGCACGAGGTGGAGGGCGTGTTGTCGCAGGTGGACTTCTT GCAACAGGTTAACGTGTATGGCGTGTGCGTGCCAGGTTGTGAGGGTAAGGTG GGCATGGCTGCTGTGCAGCTAGCCCCCGGCCAGACTTTCGACGGGGAGAAGT TGTACCAGCACGTTCGCGCTTGGCTCCCTGCCTACGCTACCCCCCATTTCATC CGCATCCAGGACGCCATGGAGGTCACCAGCACGTTCAAACTGATGAAGACCC GGTTGGTGCGTGAGGGCTTCAATGTGGGGATCGTGGTTGACCCTCTGTTTGTA CTGGACAACCGGGCCCAGTCCTTCCGGCCCCTGACGGCAGAAATGTACCAGG CTGTGTGTGAGGGAACCTGGAGGCTCTGA (SEQ NR: 7) Homo sapiens solute carrier family 27 member 5 (SLC27A5), transcript variant 2, mRNA NCBI Reference Sequence: NM_001321196.2 Ensemble Reference: ENST00000601355.1 SLC27A5-207 ATGGGTGTCAGGCAACAGTTGGCCTTGCTGCTGCTGCTGCTGCTCCTGCTCTG GGGCCTGGGGCAGCCAGTGTGGCCAGTCGCTGTGGCCTTGACCCTGCGCTGG CTCCTGGGGGATCCCACATGTTGCGTGCTACTTGGGCTGGCCATGTTAGCACG GCCCTGGCTCGGCCCCTGGGTGCCCCATGGGCTGAGCCTGGCAGCTGCGGCC CTGGCACTAACCCTCCTGCCAGCACGGCTGCCCCCAGGACTACGCTGGCTGCC GGCTGATGTGATCTTCTTGGCCAAGATCCTCCACCTGGGCCTGAAGATCAGGG GATGCTTGAGCCGGCAGCCGCCTGACACCTTTGTAGATGCCTTCGAGCGGCGA GCACGAGCGCAGCCTGGCAGGGCACTCTTGGTGTGGACGGGGCCTGGGGCCG GCTCAGTCACCTTTGACCTCCGGGAGAGCCTGGAGGAGATCCTTCCCAAGCTG CAGGCTGAGAACATCCGCTGCTTCTACCTCAGCCATACCTCCCCTACACCAGG GGTGGGGGCTCTGGGGGCTGCCCTGGATGCAGCGCCCTCCCACCCAGTGCCT GCTGACCTGCGTGCTGGGATCACATGGAGAAGCCCTGCCCTCTTCATCTATAC CTCGGGGACCACTGGCCTCCCGAAGCCAGCCATCCTCACGCATGAGCGGGTA CTGCAGATGAGCAAGATGCTGTCCTTATCTGGGGCCACAGCTGATGATGTGGT TTACACGGTCCTGCCTCTGTACCACGTGATGGGACTTGTCGTTGGGATCCTCG GCTGCTTAGATCTCGGAGCCACCTGTGTTCTGGCCCCCAAGTTCTCTACTTCC TGCTTCTGGGATGACTGTCGGCAGCATGGCGTGACAGTGATCCTGTATGTGGG CGAGCTCCTGCGGTACTTGTGTAACATTCCCCAGCAACCAGAGGACCGGACAC ATACAGTCCGCCTGGCAATGGGCAATGGACTACGGGCTGATGTGTGGGAGAC CTTCCAGCAGCGCTTCGGTCCTATTCGGATCTGGGAAGTCTACGGCTCCACAG AAGGCAACATGGGCTTAGTCAACTATGTGGGGCGCTGCGGGGCCCTGGGCAA GATGAGCTGCCTCCTCCGAATGCTGTCCCCCTTTGAGCTGGTGCAGTTCGACA TGGAGGCGGCGGAGCCTGTGAGGGACAATCAGGGCTTCTGCATCCCTGTAGG GCTAGGGGAGCCGGGGCTGCTGCTGACCAAGGTGGTAAGCCAGCAACCCTTC GTGGGCTACCGCGGCCCCCGAGAGCTGTCGGAACGGAAGCTGGTGCGCAACG TGCGGCAATCGGGCGACGTTTACTACAACACCGGGGACGTACTGGCCATGGA CCGCGAAGGCTTCCTCTACTTCCGCGACCGCCTCGGGGACACCTTCCGATGGA AGGGCGAGAACGTGTCCACGCACGAGGTGGAGGGCGTGTTGTCGCAGGTGGA CTTCTTGCAACAGGTTAACGTGTATGGCGTGTGCGTGCCAGGTTGTGAGGGTA AGGTGGGCATGGCTGCTGTGCAGCTAGCCCCCGGCCAGACTTTCGACGGGGA GAAGTTGTACCAGCACGTTCGCGCTTGGCTCCCTGCCTACGCTACCCCCCATT TCATCCGCATCCAGGACGCCATGGAGGTCACCAGCACGTTCAAACTGATGAAG ACCCGGTTGGTGCGTGAGGGCTTCAATGTGGGGATCGTGGTTGACCCTCTGTT TGTACTGGACAACCGGGCCCAGTCCTTCCGGCCCCTGACGGCAGAAATGTACC AGGCTGTGTGTGAGGGAACCTGGAGGCTCTGA (SEQ NR: 8) Homo sapiens solute carrier family 27 member 5 (SLC27A5), transcript variant 3, mRNA Ensemble Reference: ENST00000594786.1 SLC27A5-204 ATGGCTGCTGTGCAGCTAGCCCCCGGCCAGACTTTCGACGGGGAGAAGTTGT ACCAGCACGTTCGCGCTTGGCTCCCTGCCTACGCTACCCCCCATTTCATCCGC ATCCAGGACGCCATGGAGGTCACCAGCACGTTCAAACTGATGAAGACCCGGTT GGTGCGTGAGGGCTTCAATGTGGGGATCGTGGTTGACCCTCTGTTTGTACTGG ACAACCGGGCCCAGTCCTTCCGGCCCCTGACGGCAGAAATGTACCAGGCTGT GTGTGAGGGAACCTGGAGGCTCTGA (SEQ NR: 9) See also Figure 12 for mRNA coding sequences and polypeptide sequences of SLC27A5. The inhibitor is able to modulate the expression of the BAAT / SLC27A5 gene(s) or the activity of the BAAT / SLC27A5 gene product(s). A gene product can be RNA (such as mRNA, rRNA, tRNA, and structural RNA) or protein. In one embodiment, the inhibitor is an inhibitory oligonucleotide selected from an isolated or synthetic antisense RNA or DNA, siRNA or siDNA, miRNA, miRNA mimics, DNA/RNA aptamers, shRNA or DNA and chimeric antisense DNA or RNA, preferably siRNA. In a preferred embodiment, the inhibitory RNA is selected from a shRNA, gRNA, sgRNA, siRNA, miRNA, miRNA mimic or chimeric antisense RNA. According to the invention, inhibitors of BAAT / SLC27A5 may comprise an antisense RNA, siRNA, shRNA, miRNA, ribozyme, DNAzyme or other nucleic acid molecules. Such agents are typically isolates or non- naturally occurring and are made synthetically or recombinantly. The BAAT / SLC27A5 -targeting polynucleotide may be comprised in a vector. The vector may be a viral vector or a non-viral vector. Any suitable viral or non- viral liver-targeting vector may be employed. An adenoviral, adeno- associated viral or lentiviral vector, for example, is useful for this purpose but nanoparticles may also serve this function. In a preferred embodiment, the BAAT / SLC27A5 -targeting polynucleotide is comprised in a non-viral based delivery system. For example, use is made of a non-viral delivery system for RNA therapeutics known in the art. See for example Paunovska et al. (Nature Reviews Genetics volume 23, pg.265–280 (2022). These involve synthetic materials that encapsulate RNA, such as polymers, lipids and lipid nanoparticles (LNPs). In some embodiments, the BAAT / SLC27A5 -targeting polynucleotide is delivered using an LNP which have been increasingly recognized as a promising delivery system for siRNA due to their biocompatibility and the ease of large-scale production. Typically, a LNP formulation consists of a cationic lipid, a neutral lipid and/or cholesterol and a PEG-lipid. Of particular relevance for the present invention are LNPs that have a preferential uptake by the liver, such as LNPs incorporating the lipid containing tris(2-aminoethyl)amine (TREN) and 3 linoleyl chain, termed TRENL3, optionally further containing unsaturated fatty acid (Yu et al., Biomaterials.2012 Sep; 33(25): 5924–5934).Further siRNA carriers for use in the present invention are lipopeptide nanoparticles as described by Dong et al. (PNAS, February 10, 2014, 111 (11) 3955-3960). In other embodiments, liver targeting may be achieved by simple conjugation to a liver specific moiety e.g. N-acetylgalactosamine (GalNAc) or a hydrophobic lipid moiety. Tris-GalNAc binds to the Asialoglycoprotein receptor (ASGPR) that is predominantly expressed on hepatocytes resulting in rapid endocytosis. By optimising the chemistry at the 2′ position of the nucleotides and replacing phosphodiester bonds with phosphorothioate bonds, the GalNAc-oligo conjugate becomes stable enough to reach the target cells after intravenous or subcutaneous administration. In a preferred embodiment, a BAAT or SLC27A5 targeting siRNA is conjugated to a trimer of GalNAc (Springer et al. Nucleic Acid Ther.2018 Jun 1; 28(3): 109–118). In some embodiments, siRNA is conjugated to a hydrophobic lipid moiety such as cholesterol or a fatty acid e.g. docosanoic acid (DCA). Lipid conjugates may suitably be attached to the inhibitory nucleic acid through a commercially available carbon-based linker to the 3′-end of the sense strand via an amide bond. In one embodiment, BAAT and/or SLC27A5 is/are inhibited using antisense technology. One advantage of antisense technology in the treatment of a disease or condition that stems from a disease-causing gene is that it is a direct genetic approach that has the ability to modulate expression of specific disease-causing genes in a highly specific manner. Generally, the principle behind antisense technology is that an antisense compound hybridizes to a target nucleic acid and affects modulation of gene expression activity or function, such as transcription, translation, splicing or RNA stability. The modulation of gene expression can be achieved by, for example, target degradation or occupancy-based inhibition. Hence, antisense technology is an effective means for inhibiting bile acid conjugation and/or reconjugation via reducing the expression of BAAT and/or SLC27A5 and, if desired, one or more further specific gene product(s). Chemically-modified nucleosides are routinely used for incorporation into antisense compounds to enhance one or more properties, such as nuclease resistance, pharmacokinetics or affinity for a target RNA. Accordingly, in one embodiment, the invention provides an antisense oligonucleotide (ASO), typically 8 to 50 nucleotides in length, which is targeted to mRNA encoding human BAAT to suppress BAAT expression. Also provided is an ASO, typically 8 to 50 nucleotides in length, which is targeted to mRNA encoding human SLC27A5 and which is capable to suppress SLC27A5 expression. In one embodiment, the antisense oligonucleotide is about five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 nucleotides or more in length. The ASO may be targeted to a translation initiation site, 3' untranslated region, coding sequence (cds) or 5' untranslated region of mRNA encoding human BAAT or SLC27A5. The ASO may target any portion of transcript involved in the process of translating the human BAAT gene into the BAAT protein, or the human SLC27A5 gene into the SLC27A5 protein, or any of its transcript variants/isoforms. The ASO is suitably comprised in a pharmaceutically acceptable carrier. Exemplary ASO’s targeting human BAAT or human SLC27A5 according to the present invention may comprise or consist of one of the sequences provided in Tables 1-8 (see Examples 5 and 6 herein below) and Figure 10A. All native ASOs are quickly rendered useless by nuclease activity, both in vivo and in vitro. In vivo, though both endonucleases and exonucleases may lead to degradation, exonucleases appear to be most active in this degradation process. To be effective, the ASOs require chemical modification to resist nuclease degradation. Numerous nucleic acid analogs are available for modifying ASOs accordingly. For example, the ASO may have at least one phosphorothioate (PS) linkage. This modification was among the few that was considered first-generation. PS-ASOs are nuclease-resistant and therefore have longer plasma half-lives compared to all-native ASOs. In addition, they retain negative backbone charges, which facilitates PS-ASO entry into the cells. Interestingly, PS appears to have a bigger impact on transport and entry into the cell than it does on nuclease resistance. In another embodiment, the ASO is methylated. This modification was among the few that are considered second-generation. When combined with PS in ASOs, 2'-OMe-RNA has been found to improve upon the benefits of PS alone, i.e. increased nuclease resistance, plasma half-life, and tissue uptake. Inhibitors of BAAT or SLC27A5 may be conjugates of the molecules described herein. For example, the inhibitor may comprise one or more targeting ligands selected from the group consisting of cholesterol, biotin, vitamins, galactose derivatives or analogs, lactose derivatives or analogs, N-acetylgalactosamine a derivative or analog, an N- acetylglucosamine derivative or the like, and any combination thereof. In a specific aspect, the invention provides a GalNAc-conjugated siRNAs or antisense oligonucleotide capable of targeting BAAT or SLC27A5. In a further embodiment, BAAT or SLC27A5 is silenced using the RNA-guided CRISPR-Cas system, which has emerged as a promising platform for programmable targeted gene regulation. The CRISPR-associated nuclease is a non-specific endonuclease. It is directed to the specific BAAT or SLC27A5 DNA locus by a gRNA, where it makes a double-strand break. There are several versions of Cas nucleases isolated from different bacteria. The most commonly used one is the Cas9 nuclease from Streptococcus pyogenes. Of particular interest are the systems reviewed by Rittiner et al., (Front Bioeng Biotechnol.2022; 10: 1035543), is the use of a system involving nuclease-dead/inactive Cas9 (dCas9) e.g., fused to transcriptional repressors. In a specific aspect, the inhibitor is a gRNA which targets BAAT or SLC27A5. Preferably, said gRNA is comprised in a viral vector, like an adeno-associated virus (AAV) vector, for example AAV serotype 8. Exemplary gRNA sequences of the invention include those targeting human exon-1 or 2 of BAAT or SLC27A5. For example, provided herein are the gRNA’s (5’ ^3’) ACCTGGTGTCACACGAATTAAGG, CCAGTGCATATCCGAGCTACAGG, ACCTTAATTCGTGTGACACCAGG, CTCACAGGGGTAGCTGTCAACTGGAT, TCCAGTTGACAGCTACCCCTGTGAGT, TCAAGCCCACTATAGGGCCAATGAAT (SEQ NR: 10) targeting BAAT. Also provided are the gRNA’s CCCACATGTTGCGTGCTACTTGG (SEQ NR: 11), CCAAGTAGCACGCAACATGTGGG (SEQ NR: 11), CCCAAGTAGCACGCAACATGTGG (SEQ NR: 12), CCCAAGTAGCACGCAACATGTGGGAT (SEQ NR:13), CCACCTGGGCCTGAAGATCAGGGGAT (SEQ NR: 14), and AGCCATACCTCCCCTACACCAGGGGT (SEQ NR: 15) targeting SLC27A5 and uses thereof. In a further aspect, the invention provides an inhibitor that acts as a transcriptional downregulator, suppressor or deactivator of the BAAT / SLC27A5 gene(s) or protein(s), in particular for use in a method of treating a disease related to systemic and/or hepatic accumulation of bile acids. Preferably, said disease is caused by decreased bile salt export or secretion, for example by a defective bile salt export pump. Target gene downregulation or deactivation includes processes that decrease transcription of a gene or translation of mRNA. Examples of processes that decrease transcription include those that facilitate degradation of a transcription initiation complex, those that decrease transcription initiation rate, those that decrease transcription elongation rate, those that decrease processivity of transcription and those that increase transcriptional repression. Gene downregulation can include reduction of expression below pre-treatment levels. Examples of processes that decrease translation include those that decrease translational initiation, those that decrease translational elongation and those that decrease mRNA stability. Gene downregulation includes any detectable decrease in the production of a target gene product. Inhibiting the expression of the BAAT or SLC27A5 target gene may comprise any level of inhibition of said gene, for example, at least partial inhibition, such as at least about 20% inhibition, of the expression of said target gene. In some embodiments, the inhibition is at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. In certain embodiments, the invention comprises the use of an inhibitor causing a target gene product decrease by at least 20%, preferably at least 30%, more preferably at least 50% such as over 60% or over 75%, as compared to a control (such as an amount of BAAT-gene expression in a vector-transduced or transformed cell, organ or animal). Accordingly, in one aspect of the invention the inhibitor is capable of down- regulating or inhibiting BAAT expression or BAAT activity. Preferably, said downregulation/inhibition is organ-specific downregulation/inhibition. Provided herein is a BAAT-inhibitor capable of down-regulating or inhibiting BAAT expression and/or BAAT activity in the liver. Preferred inhibitors include a peptide, a peptidomimetic, a small molecule inhibitor, an antibody, an inhibitory (antisense) oligonucleotide, or a polypeptide molecule. In one embodiment it is a polypeptide molecule or a peptidomimetic. In another embodiment, it is a small molecule inhibitor. In a preferred embodiment, the inhibitor is a nucleic acid based inhibitor targeting BAAT or SLC27A5. In a specific aspect, the inhibitor is an inhibitory oligonucleotide selected from an isolated or synthetic antisense RNA or DNA, guide RNA (gRNA), siRNA or siDNA, miRNA, miRNA mimics, shRNA or DNA and chimeric antisense DNA or RNA. For example, it is a guide RNA (gRNA) or siRNA targeting BAAT or a guide RNA (gRNA) or siRNA targeting SLC27A5. siRNAs as described herein are capable of reducing or inhibiting the expression of a target gene or a target sequence. As described herein siRNAs are capable of pairing with mRNA transcript of a target gene or at least with one or more sequences within said mRNA transcript. In other words, target sequence may be a full mRNA transcript of the target gene or a sequence within said mRNA transcript. In particular, siRNAs as described herein may bind to BAAT mRNA (SEQ ID NO: 14) or SLC27A5 mRNA (SEQ ID NO: 19). siRNAs as described herein may bind to one or more target sequences within BAAT mRNA or to one or more target sequences within SLC27A5 mRNA selected from Table 1. Table1: Examples of target sequences Target sequence SEQ NR Sequence (5’ to 3’ direction) Target 16 AAGGTGATAAGACTATCAACA sequences 17 AAGTCACAGCCACGGTACTTATT within BAAT 18 AAACCAGAAGTAACAGATTTG mRNA Target 19 AAGAGACATGGGAAGAACAAC sequences within SLC27A5 20 AACGACCCACGATTTGAGGTT mRNA The length of an siRNA as described herein is typically between 15 to 30 nucleotides. The sense and antisense strands may be of the same length, or they may be of different lengths. The sense and antisense strands of siRNAs as described herein may each be of 15-30 nucleotides in length. In some embodiments, the sense and antisense strands are each independently of 17- 25 nucleotides in length, preferably of 19-23 nucleotides in length. In some embodiments, the sense and antisense strands of the siRNA are each independently of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the antisense strand is of 19-21 nucleotides in length and the sense strand is of 19-23 nucleotides in length. In some embodiments, the antisense strand is of about 21 nucleotides in length and the sense strand is of about 21 nucleotides in length. In some embodiments, the antisense strand is of about 21 nucleotides in length and the sense strand is of about 23 nucleotides in length. Methods of preparing siRNA are well known in the art. In some embodiments, the siRNA is prepared or provided as a salt, a mixed salt, or a free acid. In some embodiments, the siRNA is prepared as a sodium salt. Examples of nucleotide sequences of sense and antisense strands used to form siRNAs are provided in Table 2. Preferably, the siRNA as described herein comprises a sense strand sequence having SEQ NO: 21, 23 or 25. Preferably, the siRNA as described herein comprises An antisense strand sequence having SEQ NO: 22, 24 or 26. More preferably, the BAAT siRNA as described herein comprises an antisense strand sequence and a sense strand sequence pair as depicted in Table 2, in particular BAAT siRNA_1, siRNA_2 or siRNA_3. In some embodiments, the antisense strand of the siRNAs disclosed herein differs from any one of the antisense strand sequences shown in Table 2 by 1, 2, or 3 nucleotides. In some embodiments, the sense strand of the siRNAs disclosed herein differs from any one of sense strand sequences shown in Table 2 by 1, 2, or 3 nucleotides. Table 2: Nucleotide sequences of sense strands (SS) and antisense strands (AS) of BAAT siRNAs BAAT SEQ Strand Sequence siRNA NO: _1 21 SS 5’- GGUGAUAAGACUAUCAACATT-3’ 22 AS 3’-TTCCACUAUUCUGAUAGUUGU-5’ _2 23 SS 5’-GUCACAGCCACGGUACUUAUU-3’ 24 AS 3’-UUCAGUGUCGGUGCCAUGAAUAA-5’ _3 25 SS 5’- ACCAGAAGUAACAGAUUUGTT-3’ 26 AS 3’- TTUGGUCUUCAUUGUCUAAAC-5’ siRNA(s) as described herein may be modified. The phrase “modified siRNA” refers to a siRNA wherein a sense strands and/or an antisense strand of said siRNA is modified by the substitution of at least one nucleotide with a modified nucleotide. A modified siRNA may be advantageously more thermally stable, may have increased resistance against nuclease degradation, and/or may have increased efficacy compared to a non-modified siRNA. In particular, modifications may increase nuclease resistance of siRNA and ensure a longer half-life in the cellular environment. Modified siRNA(s) may comprise one or more modified nucleotides. The chemical modification may comprise replacing or substitution an atom of a pyrimidine base with an amine, SH, an alkyl (e.g., methyl, or ethyl), or a halogen atom (e.g., chloro or fluoro). The chemical modification may also comprise modifications of the sugar moiety and/or phosphate backbone. Preferably, modified nucleotides of said siRNA are sugar-modified and/or backbone-modified nucleotides. Ribose modifications affecting the 2’OH group are the most effective in blocking endoribonucleases, which make the main contribution to siRNA cleavage, whereas phosphate modifications block exonucleases better. The cleavage mechanism by endonucleases involves the 2’OH group of the ribose, so replacement of all this group with a 2’F fluorine or 2’O-Me group is necessary throughout the duplex. The sugar-modified nucleotides include, but are not limited to: a 2'- O-methyl (also referred herein as 2’-OMe) modified nucleotide, a 2'- deoxynucleotide, a 2'-deoxy-2’-fluoro modified nucleotide, a 2'-fluoroarabino modified nucleotide a 2'-methoxyethyl (also referred herein as 2’-MOE) modified nucleotide, a 2'-amino modified nucleotide, a 2'-alkoxy modified nucleotide, a 2'-alkyl modified nucleotide, a locked nucleotide, and an unlocked nucleotide. In particular, examples of 2’-OMe modified nucleotide include 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'- phosphate, 2'-O-methylguanosine-3'-phosphate, 2'-O-methyluridine-3'- phosphate. Examples of 2’-deoxynucleotide include 2'-deoxyadenosine-3'- phosphate, 2'-deoxycytidine-3'-phosphate, 2'-deoxythymidine-3'-phosphate, 2'-deoxyuridine-3'-phosphate. In particular, 2'-deoxythymidine-3'-phosphate comprises sugar modification (i.e.2’-deoxyribose) as well as base modification (i.e. thymine, also known as 5-methyluracil) compared to a standard uridine-3’-phosphate normally found in RNA. Examples of 2’-fluoro modified nucleotide include 2'-fluoroadenosine-3'-phosphate, 2'- fluorocytidine-3'-phosphate, 2'-fluoroguanosine-3'-phosphate, 2'- fluorouridine-3'-phosphate. It is not necessary to modify all nucleotides in given siRNA(s) uniformly. Rather, one or more modifications can be added to a single siRNA, a single strand of siRNA (i.e. sense or antisense strand) or even to a single nucleotide thereof. The modification of one nucleotide is independent of the modification of another nucleotide. One or more modifications are preferably added to both strands of siRNA. Preferably, the sugar-modified nucleotides of siRNA are selected from the group consisting of a 2'-O-methyl (also referred herein as 2’-OMe) modified nucleotide, a 2'- deoxynucleotide, a 2'-deoxy-2’-fluoro modified nucleotide, or a combination thereof. Nucleotides are typically linked by a phosphodiester bond (also referred herein as a standard linkage or backbone). Nucleotides of siRNA may also be backbone-modified nucleotides. The phrase “backbone-modified nucleotide” refers to a nucleotide that is linked by a non-standard linkage or backbone. In other words, said non-standard linkage is a modified internucleoside linkage or a modified backbone. The modified internucleoside linkage or backbone includes, but is not limited to, a phosphorothioate group, a chiral phosphorothioate group, a phosphorodithioate group, a boranophosphate group, an alkyl phosphonate group (e.g. methylphosphonate group, methoxypropylphosphonate group), a thioalkyl phosphonate group, an amide group, a phosphinate group, a phosphoramidate group, and a morpholino linkage. Preferably, the backbone-modified nucleotide comprises a phopshorothioate group. Sense and antisense strands may comprise the same or different amount of backbone-modified nucleotides. The one or more modified internucleoside linkages may be located between nucleotides at positions 1-3 from the 5' end, from the 3' end or on both ends of either strand (i.e. sense and antisense strand). The modified internucleoside linkage may be located between nucleotides at positions 1-2 from the 5' end, from the 3' end or on both ends of either strand (i.e. sense and antisense strand). The modified internucleoside linkage may be located between nucleotides at positions 2-3 from the 5' end, from the 3' end or on both ends of either strand (i.e. sense and antisense strand). Preferably, sense and antisense strands comprise two modified internucleoside linkages on both ends. Preferably, a modified siRNA comprises sugar-modified and backbone-modified nucleotides as described herein. More preferably, a modified siRNA comprises at least one or more nucleotides comprising a phosphorothioate group, and at least one or more sugar-modified nucleotides selected from the group consisting of 2'-O-methyl modified nucleotide, 2'-deoxynucleotide, 2'-deoxy-2’-fluoro modified nucleotide, or a combination thereof. In some embodiments, the inhibitor of the present invention is advantageously combined with (e.g. by simultaneous or separate co- administration of) a further therapeutically effective agent selected from UDCA, bile acid sequestrants (BAS) such as colesevelam/cholestyramine, antihistamine agents (e.g., hydroxyzine, diphenhydramine), rifampin, naloxone, prednisone, azathioprine, methotrexate, 6-mercaptopurine, mesalazine, phenobarbital, dronabinol (CB 1 agonist), methotrexate, corticosteroids, cyclosporine, chaperones, potentiators, ileal bile acid transporter (IBAT) inhibitors, FXR agonists, FGF19-mimetics, FGFR4 agonists, PPARalfa agonists, colchicines, TPGS - vitamin A, D, E, or K optionally with polyethylene glycol, zinc. Other further therapeutic agents include probiotics (selective strains of bacteria), and prebiotics. The inhibitor according to the invention is advantageously used in combination with one or more further regulator(s) / inhibitor(s) of bile acid metabolism. For example, the inhibitor may be used in combination (therapy) with bile acid sequestrant and/or an IBAT inhibitor. The invention also provides the use of bile acid-CoA:amino acid N- acyltransferase (BAAT) and/or the SLC27A5 gene or gene product, as molecular target in a method of reducing liver damage in a human subject. In a further embodiment, the invention provides a method of stimulating/enhancing bile flow in a subject, comprising targeting the acid- CoA:amino acid N-acyltransferase (BAAT) and/or the SLC27A5 gene or gene product. Preferably, BAAT and/or SLC27A5 is targeted exclusively in the liver. Suitably, the subject is a human subject, for example said human subject is an infant. In some cases, the subject is an infant less than 2 years of age. In some cases, for any of the uses, methods and/or compositions described herein, the infant is between 0 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 4 to 18 or 6 to 18 months of age. In other cases, the infant is between 18 to 24 months of age. In some instances, for any of the methods and/or compositions described herein, the individual is a child of between about 2 to about 10 years of age. In other instances, the individual is more than 10 years old. In some cases, the individual is an adult. Targeting of BAAT and/or SLC27A5 in the liver of a subject can be accomplished using one of the various strategies that have been proposed to improve the delivery of different drugs to liver and hepatocytes. These include passive accumulation of nanoparticle therapeutics and active targeting by surface modifications of nanoparticles with specific ligands such as carbohydrates, peptides, proteins and antibodies. Ligand-mediated approaches for targeting BAAT and/or SLC27A5 in the liver may involve the targeting of one or more of Mannose – 6 –phosphate receptor (by Mannose-6- phosphate), Type VI collagen receptor (e.g. by Cyclic RGD), the PDGF receptor (by PDGF), Scavenger receptor class A (e.g. by Human serum albumin), the Asialoglycoprotein receptor (e.g. by Galactoside or Galactosamine), the Plasma membrane fatty acid binding protein (putative) (e.g. by Linoleic acid), the Scavenger receptor class B type I (e.g. by Apolipoprotein A-I), Heparan sulfate (e.g. by Acetyl CKNEKKNKIERNNKLKQPP-amide), the IL-6-receptor and/or immunoglobulin A binding protein (Putative) (e.g. by Pre-S1) and Glycyrrhizin receptors (by Glycyrrhizin). As is clear from the above, the invention relates to a diverse range of compounds capable of inhibiting bile acid conjugation and/or reconjugation, for use as a medicament. The inhibitor of bile acid conjugation and/or reconjugation is suitably used in a method of alleviating symptoms and decreasing organ (e.g. liver) damage in a subject, in particular in a subject suffering from a condition characterized by (or associated with) accumulation of bile acids. For example, the condition is characterized by systemic and/or hepatic accumulation of bile acids. In one aspect, it is associated with elevated levels of systemic (serum) bile acid. In another aspect, it is associated with increased levels of intrahepatic bile acids. In yet another aspect, the condition is characterized by the accumulation of systemic and intrahepatic bile acids. Also provided is a method of treating a disease associated with hepatic accumulation of bile acids and hepatocellular inflammation. In one embodiment, the inhibitor is used in a method of treating a disease related to systemic and/or intrahepatic accumulation of bile acids. Hence, the invention also provides a method of treating a disease related to systemic and/or intrahepatic accumulation of bile acids in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor or pharmaceutical composition according to the invention. In some embodiments, compositions and methods provided herein decrease serum or hepatic bile acid levels by at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, as compared to the levels prior to administration of the compositions provided herein or as compared to control subjects. In some embodiments, methods provided herein decrease serum or hepatic bile acid levels by at least 30%. In some embodiments, methods provided herein decrease serum or hepatic bile acid levels by at least 25%. In some embodiments, methods provided herein decrease serum or hepatic bile acid levels by at least 20%. In some embodiments, methods provided herein decrease serum or hepatic bile acid levels by at least 15%. Preferably, compositions and methods provided herein decrease hepatic bile acid levels by at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, as compared to the levels prior to administration of the compositions provided herein or as compared to control subjects. In some embodiments, methods provided herein decrease hepatic bile acid levels by at least 30%. In some embodiments, methods provided herein decrease hepatic bile acid levels by at least 25%. In some embodiments, methods provided herein decrease hepatic bile acid levels by at least 20%. In some embodiments, methods provided herein decrease hepatic bile acid levels by at least 15%. In one aspect, the condition or disease is caused by a defective bile salt export pump (PFIC2). The condition or disease may be, but not necessarily is, a genetic disease. The disease may be a pediatric liver disease. In one embodiment, the condition is characterized or complicated by systemic and/or hepatic accumulation of bile acids, such as cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH), and other diseases with bile acid-induced or bile acid-impacted liver damage/fibrosis and hepatocellular inflammation. Thus, the invention also provides an inhibitor of bile acid conjugation and/or reconjugation, for use in a method of for alleviating symptoms and decreasing organ (e.g. liver) damage in a subject suffering from NASH, also known in the art as metabolic dysfunction-associated steatohepatitis (MASH). In a preferred embodiment, this method involves the use of a (nucleic acid based) inhibitor that suppresses or inhibits the expression or activity of BAAT. In a preferred embodiment, the condition is a cholestatic liver disease (CLD), for example selected from the group consisting of Progressive Familial Intrahepatic Cholestasis (PFIC) types, syndromic (Alagille syndrome), on non-syndromic paucity of bile ducts, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), obstructive cholestatic liver diseases and biliary atresia. Cholestasis is considered an impairment of one of many steps involved in the synthesis, secretion, and modification of bile acids, resulting in liver damage. Cholestasis can be due to a functional impairment of the hepatocytes in the secretion of bile and/or due to an obstruction at any level of the excretory pathway of bile. Genetic diseases of cholestasis include, in addition to progressive familial intrahepatic cholestasis (PFICs), progressive familial hypercholanemia and bile acid synthesis defects (BASD). In one specific aspect, the disease is Progressive Familial Intrahepatic Cholestasis (PFIC), which can be classified into PFIC1-6. PFIC1-3 are caused by defects in the ATP8B1 gene encoding the familial intrahepatic cholestasis 1 (FIC1) protein, the ABCB11 gene encoding bile salt export pump (BSEP) protein, or the ABCB4 gene encoding multidrug resistance (MDR3) protein, respectively. More recently, defined mutations in TJP2 (encoding the tight junction protein ZO-2), NR1H4 (encoding the farnesoid X receptor, FXR) and MYO5B (encoding Myosin-Vb) were identified to underlie PFIC 4, 5 and 6, respectively. Furthermore, a number of other genes has been identified that may represent putative new PFIC genes. In one embodiment, the invention provides a pharmaceutical composition comprising an inhibitor of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or gene product, and a pharmaceutically acceptable carrier, vehicle or diluent. Preferably, the pharmaceutical composition comprises a BAAT-inhibitor capable of down-regulating or inhibiting BAAT expression and/or BAAT activity, in particular a BAAT-inhibitor that is capable of down-regulation or inhibition of BAAT in the liver. In another embodiment, the invention provides a pharmaceutical composition comprising an inhibitor of the SLC27A5 gene or gene product, and a pharmaceutically acceptable carrier, vehicle or diluent. Preferably, the pharmaceutical composition comprises a SLC27A5-inhibitor capable of down-regulating or inhibiting SLC27A5 expression and/or SLC27A5 activity, in particular a SLC27A5-inhibitor that is capable of down- regulation or inhibition of SLC27A5 in the liver. Also envisaged is a pharmaceutical composition comprising an inhibitor of BAAT as well as an inhibitor of SLC27A5. Exemplary pharmaceutical compositions comprising an inhibitor for targeting the BAAT or SLC27A5 gene include nucleic acid based inhibitors. Suitable inhibitors for targeting BAAT or SLC27A5 proteins include DAN/RNA-based aptamers. In a specific aspect, the invention provides a pharmaceutical composition comprising a BAAT- and/or SLC27A5- inhibitory oligonucleotide selected from an isolated or synthetic antisense RNA or DNA, guideRNA (gRNA), siRNA or siDNA, miRNA, miRNA mimics, DNA/RNA aptamers, shRNA or DNA and chimeric antisense DNA or RNA. Suitably, said oligonucleotide, e.g. siRNA or gRNA, is comprised in a nanoparticle (NP), preferably a lipid nanoparticle (LNP). For example, the pharmaceutical composition comprises one or more siRNA or a gRNA molecules that inhibit expression (target) BAAT and/or SLC27A5. Preferably, the pharmaceutical composition comprises a siRNA or a gRNA targeting BAAT and/or a siRNA or a gRNA targeting SLC27A5. The pharmaceutical composition may comprise one or more further active ingredients, preferably additional inhibitor(s) of intestinal bile acid reuptake and/or inhibitor(s) of hepatic bile acid synthesis, such as a bile acid sequestrant and/or an IBAT inhibitor and/or an FXR agonist and/or a FGF19 mimetic. LEGEND TO THE FIGURES Figure 1. (A) Alanine aminotransferase (ALT) and (B) aspartate aminotransferase (AST) in plasma of female Cyp2c70-KO/Cas9tg mice at 3 weeks after injection with AAV-sgControl (sgCtrl) or AAV-sgBaat. * p<0.05 using Mann-Whitney U test. Figure 2. (A) Liver and (B) spleen weight of female Cyp2c70-KO/Cas9tg mice at 6 weeks after injection with control virus (AAV-sgCtrl) or AAV- sgBaat expressed as percentage of body weight. * p<0.05 using Mann- Whitney U test. Figure 3. Sections (4 µm) of formalin-fixed paraffin-embedded livers were stained with (top panels) hematoxylin & eosin for gross morphology or (bottom panels) with Sirius Red and Fast Green to visualize fibrosis. Representative images are depicted, demonstrating that inactivation of the Baat gene (right hand panels) improves liver morphology and reduced fibrosis in female Cyp2c70-KO/Cas9tg mice. Size bar indicates 200 µm. Figure 4. Female Cyp2c70-KO/Cas9tg mice were injected with AAV-sgCtrl or AAV-sgBaat and gallbladder cannulations were performed 6 weeks after injection to study the impact of inhibition of bile acid conjugation on bile formation. After the bile duct had been ligated, the gallbladder was cannulated and mice were placed into a humidified incubator (37 ^oC) during bile collection. Bile was collected continuously for 30 minutes. (A) The percentage of unconjugated bile acids in the bile as determined by LC- MS/MS. (B) Bile flow. (C) Total biliary bile acid concentrations as determined by LC-MS/MS. (D) Biliary bile acid secretion rates. (E) Correlation of the percentage of unconjugated bile acids in the bile with bile flow. (F) Correlation of the percentage of unconjugated bile acids in the bile with biliary total bile acid concentrations. *** p<0.001 using Mann-Whitney u test. BA, bile acid. Figure 5. CRISPR/Cas9-mediated inactivation of the Abcb4 gene in livers of mice heterozygous for Cyp2c70 (Cyp2c70-HET; which have a normal murine bile acid composition, that is indistinguishable from wildtype mice) hardly causes any liver damage at 6 weeks after injection of an AAV encoding 3 different sgRNAs targeting the Abcb4 gene, while inactivation of hepatic Abcb4 in the context of a human-like bile acid composition, i.e., in Cyp2c70- KO mice causes severe liver pathology (n=5-6 mice/group). (A) Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), established markers of liver damage. (B) Representative images of sections (4 µm) of formalin-fixed paraffin-embedded livers that were stained with Sirius Red and Fast Green to visualize fibrosis. * p<0.05, ** p<0.01, *** p<0.001 using Kruskal-Wallis test followed by Conover post hoc comparisons. Figure 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma in a mouse model of PFIC3 (Cyp2c70-KO with Abcb4- KD) upon inhibition of Baat. Male Cyp2c70-KO/Cas9tg mice were injected with either AAV-sgAbcb4 + AAV-sgCtrl or with AAV-sgAbcb4 + AAV-sgBaat mice. Blood samples were taken at (A) 3 and (B) 6 weeks after virus injection for measurement of plasma transaminases. The data indicate substantially lower liver damage in the mice receiving AAV-sgBaat in addition to sgAbcb4 as compared to the mice receiving the control virus (AAV-sgCtrl) combined with sgAbcb4. * p<0.05 using Mann-Whitney U test. Figure 7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma of female Cyp2c70-heterozygous/Cas9tg and Cyp2c70-KO/Cas9tg mice injected with either AAV-sgCtrl or AAV-sgSlc27a5 determined at (A) 3 and (B) 6 weeks after virus injection. The data indicate substantially lower liver damage in Cyp2c70-KO/Cas9tg mice receiving AAV-sgSlc27a5 as compared to those receiving the control virus (AAV- sgCtrl), while there were no indications of overt liver damage caused by Slc27a5 inactivation in Cyp2c70-hetrozygous mice. Therefore, the inactivation of Slc27a5 appears to be safe as well as an effective treatment for bile acid-induced liver disease. * p<0.05, ** p<0.01, *** p<0.001 using Kruskal-Wallis test followed by Conover post hoc comparisons. Figure 8. Bile formation in mice upon inactivation of the Slc27a5 gene by CRISPR/Cas9-mediated somatic genome editing. (A) Bile flow and (B) total biliary bile acid concentrations in female Cyp2c70-heterozygous/Cas9tg and Cyp2c70-KO/Cas9tg mice injected with either AAV-sgCtrl or AAV-sgSlc27a5 mice determined at 6 weeks after virus injection. *** p<0.001 using Kruskal-Wallis test followed by Conover post hoc comparisons. Figure 9. Effects of hepatic inactivation of the Baat or Slc27a5 gene on DDC-induced cholestasis in mice. For details see Example 4.(A) Body weight development in mice injected with AAV-sgEmpty (sgEmpty), AAV-sgBaat or AAV-sgSlc27a5 fed either a control chow diet or a DDC-containing diet. Recovery periods are indicated in grey shade. (B-E) Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin in mice injected with AAV-sgEmpty (sgEmpty), AAV-sgBaat or AAV-sgSlc27a5 fed either a control chow diet or a DDC-containing diet. Figure 10. The effectivities of siRNAs targeting the coding sequence of the human BAAT gene. (A) nucleotide sequences of inhibitory siRNA_1,_2 and _3, and a control (siScrambled) siRNA. (B) location of target sequences of the siRNAs on the BAAT mRNA (C) knockdown activity of the siRNAs targeting the BAAT mRNA. For details see Example 5. Figure 11. mRNA and polypeptide sequences of Homo sapiens bile acid- CoA:amino acid N-acyltransferase (BAAT). (A) Transcript variant 1 : NM_001701.4 (B) Transcript variant 2 : NM_001127610.2 (C) Transcript variant 3 : NM_001374715.1. Figure 12. mRNA and polypeptide sequences of Homo sapiens solute carrier family 27 member 5 (SLC27A5). (A) Transcript variant 1 : NM_012254.3 (B) Transcript variant 2 : NM_001321196.2 (C) Ensemble Reference: ENST00000594786.1 . EXPERIMENTAL SECTION The Examples herein below demonstrate that severe cholestatic liver disease can be turned into a benign disease by inhibiting bile acid (re)conjugation by interfering with the expression or activity of bile acid- CoA:amino acid N-acyltransferase (BAAT) and/or solute carrier family 27 member 5 (SLC27A5). The examples make use of Cyp2c70-KO mice, which have a hydrophobic, human-like bile acid composition due to their inability to convert chenodeoxycholic acid into mouse-/rat-specific muricholic acid species. This substantially more hydrophobic bile acid composition results in cholangiopathy in these mice, which has features of primary biliary cholangitis (PBS) and primary sclerosis cholangitis (PSC). Cyp2c70-KO mice display increased levels of the liver damage markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma. Furthermore, periportal fibrosis is clearly present in Cyp2c70-KO mice, which progresses into bridging fibrosis with age in female but not in male mice. Multiple experiments were performed to illustrate the impact of inhibition of bile acid (re)conjugation on the development of bile acid-induced liver disease in mice: I. The impact of acute hepatic inactivation of the Baat gene on the development of liver pathology in female Cyp2c70-KO mice was investigated. II. The effects of acute hepatic inactivation of the Baat gene were explored in a murine model of progressive familial intrahepatic cholestasis type 3 (PFIC3), i.e., (male) Cyp2c70-KO mice with inactivation of the Abcb4 gene, encoding the hepatic phospholipid transporter MDR2 in mice (MDR3 in humans). III. The consequences of acute hepatic inactivation of the Slc27a5 gene on the development of liver pathology in female Cyp2c70-KO mice was investigated. IV. The effects of acute hepatic inactivation of the Baat or Slc27a5 genes were explored in Cas9tg mice fed a 3,5-Diethoxycarbonyl-1,4- Dihydrocollidine (DDC)-containing diet, a mouse model commonly used for PSC. V. The effectivities of inhibitory nucleic acids targeting the coding sequence of the human BAAT gene were assessed using an in vitro screening system. EXAMPLE 1: Impact of acute hepatic inactivation of the Baat gene on the development of liver pathology. To demonstrate the potential of Baat inactivation to ameliorate the bile acid-induced liver pathology present in Cyp2c70-KO mice, 12 weeks old female Cyp2c70-KO/Cas9-trangenic (Cas9tg) mice on a pure C57BL/6J background (n=8 mice/group) were injected with 1 x 10¹¹ genome copies/mouse of adeno-associated virus (AAV) encoding 3 different single- guide (sg)RNAs targeting the murine Baat gene sequence (sg1, CTGACGACTATGTCTTGTAATGG; sg2, GTAAAGGAAAGCCGCATCCGGGG; sg3, TGATGACCTGCCTTCTCGACTGG) or with a control virus containing only the scaffold sequence but no sgRNA sequences (AAV-sgCtrl). Because 12 weeks old female Cyp2c70-KO already have established liver disease, hallmarked by ductular reactions and fibrosis as well as by elevated plasma transaminases, this experiment allowed to assess the curative potential of Baat inactivation on liver disease in this mouse model. Three weeks after AAV injection, a small blood sample was taken from part of the mice (n=4 mice/group) for measurement of plasma transaminases. The levels of ALT and AST in plasma of Cyp2c70-KO/Cas9tg mice that had received the control virus were clearly elevated compared to those normally observed in wildtype C57BL/6J mice (Otto GP et al., J Am Assoc Lab Anim Sci, 2016;55(4):375-86), while the mice that had been injected with the Baat- targeting sgRNA-encoding AAV showed a very strong reduction of these liver damage markers (Figure 1). Six weeks after AAV injection, at the age of 18 weeks, the female Cyp2c70- KO/Cas9tg mice injected with either AAV-sgCtrl or AAV-sgBaat were sacrificed and blood and organs were collected for analyses. Body weights were not different between the groups (data not shown). The Cyp2c70- KO/Cas9tg female mice that had been injected with the control virus showed the increased liver weights (normally 4-5.5% in healthy wild-type C57BL6/J mice) that are typical for this mouse model (Figure 2), whereas the mice that had been injected with AAV-sgBaat showed substantially reduced liver- to-body weight ratios. Also, the spleens in the Cyp2c70-KO/Cas9tg mice injected with AAV-sgCtrl were enlarged as is normally observed in female Cyp2c70-KO mice (de Boer JF et al., Cell Mol Gastroenterol Hepatol, 2021;11(4):1045-1069). Injection of AAV-sgBaat in the Cyp2c70-KO/Cas9tg mice markedly reduced spleen sizes, suggesting a decrease in systemic inflammation. Histological examination of the livers showed the ductular reactions that are typically observed in Cyp2c70-KO mice in the animals that had been injected with AAV-sgCtrl as well as clear fibrosis (Figure 3, left panels). Both of these features were largely resolved in the mice that had been injected with AAV-sgBaat (Figure 3, right panels), indicating that inhibition of bile acid (re)conjugation restores liver pathology in this mouse model of bile acid-induced liver disease. To examine the effects of inhibition of bile acid conjugation on bile formation and biliary bile acid secretion, gallbladder cannulation was performed in female Cyp2c70-KO/Cas9tg mice that had been injected with AAV-sgCtrl or AAV-sgBaat at 6 weeks after AAV injection. Whereas nearly all biliary bile acids were conjugated in the mice that had been injected with the control virus, a substantial percentage of bile acids in the bile of the mice that had been injected with AAV-sgBaat consisted of unconjugated bile acids (Figure 4A). However, considerable amounts of conjugated bile acids were still present in the bile of these mice. This may be due to several reasons. First, incomplete inactivation of the Baat gene in the livers of the mice by the CRISPR/Cas9-mediated somatic genome editing approach, with AAV- mediated delivery of sgRNAs, that was used. Although highly efficient, some residual activity of the products of targeted genes is usually observed with this approach (Fedoseienko et al., Circ Res, 2018 Jun 8;122(12):1648-1660). Second, unlike humans mice possess two functional homologues of Baat, called acyl-coenzyme A amino acid N-acyltransferase 1 (Acnat1) and Acnat2, which were not targeted by the sgRNA sequences used in the experiments. Third, preferential transport of conjugated bile acids from the hepatocytes into the bile by the bile salt export pump (BSEP, ABCB11) may have resulted in highly efficient biliary secretion of any bile acids that were conjugated in the livers of mice injected with AAV-sgBaat, whereas unconjugated are likely to be secreted into the bile in a much less efficient manner, leading to a relative overrepresentation of conjugated bile acids in the bile of these mice (Noé J et al., Gastroenterology, 2002 Nov;123(5):1659- 66). Bile flow was substantially higher in the Cyp2c70-KO/Cas9tg mice injected with AAV-sgBaat compared to controls (Figure 4B), whereas biliary bile acid concentrations were about 60% lower (Figure 4C), indicating that the bile was more diluted in these animals. The biliary bile acid secretion rate tended to be lower in the mice injected with AAV-sgBaat (Figure 4D, p=0.08). Next, the large variation in the percentage of unconjugated bile acids present in the bile of mice injected with sgBaat (Figure 4A) was exploited to investigate whether the percentage of unconjugated bile acids in bile was related to alterations in bile formation. It was found that the percentage of unconjugated bile acids in the bile positively associated with bile flow (Figure 4E) en negatively associated with total biliary bile acid concentrations (Figure 4F), suggesting that the dilution of bile depends on the efficiency of Baat inactivation. In conclusion, inactivation of the Baat gene in livers by CRISPR/Cas9-mediated somatic genome editing using AAV-mediated delivery of sgRNAs effectively cures the liver pathology present in female Cyp2c70-KO mice, i.e., a model of bile acid-induced liver pathology with features of both PBC and PSC. EXAMPLE 2: The effects of acute hepatic inactivation of the Baat gene on progressive familial intrahepatic cholestasis type 3 (PFIC3). Phospholipids that are secreted into the bile protect the cells lining the biliary tree from damage by ‘shielding’ the bile acids by facilitating the formation of mixed micelles, thereby decreasing the exposure of the cell membranes of these cells to the detergent effects of bile acids. Humans with a deficiency in the gene encoding the biliary phospholipid transporter MDR3 (ABCB4) have an impaired ability to secrete phospholipids into the bile. Consequently, biliary bile acids are less shielded by phospholipids, increasing the exposure of the cells lining the biliary tree to the detergent effects of these bile acids, resulting in PFIC3, a disease characterized by progressive liver damage and deterioration of liver function, often necessitating liver transplantation. In mice, Abcb4-deficiency also causes liver damage, although Abcb4-KO mice display a phenotype that is milder than that of humans due to the considerably more hydrophilic bile acid composition in these animals. However, when the Abcb4 gene is inactivated in livers of Cyp2c70-KO mice with a hydrophobic, human-like bile acid composition using CRISPR/Cas9- mediated somatic genome editing (PFIC3 mice), severe liver disease is observed that resembles human PFIC3 (unpublished observations, Figure 5A, 5B). The sgRNA sequences used to inactivate the Abcb4 gene in the livers of the mice were: sg1, AAACGGAACAGCACGGCGCCTGG; sg2, CTAGTTCAAAGTCGCCGTCCAGG; sg3, CTGGACGGCGACTTTGAACTAGG). The PFIC3 mice (Cyp2c70-KO/Abcb4-KD) were used to study the effects of hepatic inactivation of the Baat gene, by CRISPR/Cas9-mediated somatic genome editing using AAV-mediated delivery of sgRNAs. In this experiment, 10-12 weeks old Cyp2c70-KO/Cas9tg mice were injected with either 1 x 10¹¹ genome copies/mouse of AAV-sgAbcb4 plus 1 x 10¹¹ genome copies/mouse of AAV-sgCtrl or with 1 x 10¹¹ genome copies/mouse of AAV- sgAbcb4 plus 1 x 10¹¹ genome copies/mouse of AAV-sgBaat. Intermediate blood samples were taken 3 weeks after AAV injection (n=4-5 mice/group). Analysis of plasma transaminases confirmed that ALT and AST levels were indeed very high in the Cyp2c70-KO/Cas9tg mice that had been injected with AAV-sgAbcb4 plus AAV-sgCtrl, but were dramatically reduced in the mice that had been injected with AAV-sgAbcb4 in combination with AAV-sgBaat at 3 weeks after virus injection (Figure 6A) as well as at 6 weeks after virus injection (n=4 mice/group, Figure 6B). EXAMPLE 3: The consequences of acute hepatic inactivation of the Slc27a5 gene on the development of liver pathology. Before bile acids can be conjugated, a acyl-CoA group needs to be attached to the molecules. For de novo synthesized bile acids, the acyl-CoA group is attached to the synthesis intermediates already, allowing BAAT to conjugate the bile acids to either glycine or taurine directly after the new bile acids have been synthesized. Bile acids that have been deconjugated by the intestinal microbiome, need to be ligated to acyl-CoA upon their return to the liver before they can be conjugated to glycine or taurine. The ligation of acyl-CoA to the recycling deconjugated bile acids is mediated by solute carrier family 27 member 5 (SLC27A5, BACS, BAL, FATP-5). Inhibition of SLC27A5 is therefore anticipated to have largely similar effects on cholestatic liver diseases as inhibition of BAAT. Hence, the Slc27a5 gene was inactivated in livers of female Cyp2c70-heterozygoes/Cas9tg as well as Cyp2c70-KO/Cas9tg mice by injecting them with an AAV encoding 3 different sgRNAs (sg1, GGATCAATCCACACAGCCGAGGG; sg2, GACCCGCTCATGTGATAAGATGG; sg3, CAAGGACAAGCCCTATCGTATGG) targeting the Slc27a5 gene sequence (AAV-sgSlc27a5). Blood samples were taken from the mice at 3 as well as 6 weeks after AAV injection to measure plasma transaminases as an indication for the degree of liver damage (Figure 7A, B). In line with earlier data, these data showed that ALT and AST were considerably elevated in Cyp2c70-KO mice as compared to Cyp2c70-heterozygous mice, which have plasma transaminase levels that are comparable to those in wildtype mice (de Boer JF et al., Cell Mol Gastroenterol Hepatol, 2021;11(4):1045-1069). Injection of Cyp2c70-KO/Cas9tg mice with AAV-sgSlc27a5, strongly reduced ALT and AST levels in plasma, indicating that inhibition of bile acid reconjugation by inactivation of the hepatic Slc27a5 gene effectively restored liver damage in this model of bile acid-induced liver pathology. These data shown that, in analogy to inactivation of Baat, inactivation of the Slc27a5 gene also translates into an increase of bile flow and a substantial decrease of the bile acid concentrations in bile (Figure 8A, B). These data suggest that stimulation of bile flow, and the therewith associated dilution of the bile, contributes to the hepatoprotective effects of Slc27a5 inactivation. Taken the data above into account, inhibition of bile acid (re)conjugation not only prevents (Example 1) but also cures (Examples 2 and 3) pathology in humanized mouse models of liver disease. The data support the novel concept that both BAAT and SLC27A5 represent targets for therapy in patients with cholestatic liver diseases or other bile acid-related liver pathologies. *** p<0.001 using Mann Whitney U test. EXAMPLE 4: The effects of acute hepatic inactivation of the Baat or Slc27a5 gene on DDC-induced cholestasis. The Baat or Slc27a5 genes were inactivated in livers of adult Cas9tg mice using CRISPR/Cas9-mediated somatic genome editing technology and AAV-mediated delivery of sgRNAs as described for Example 1-3. Two weeks later, the mice were fed a diet containing 0.1% 3,5- diethoxycarbonyl-1,4-dihydrocollidine (DDC) or a control diet. DDC diet was provided in an intermittent manner (5 days DDC diet followed by two days control diet without DDC) for 4 weeks. The last 7 days of the experiment, the DDC-treated mice received the DDC-containing diet. Blood samples were taken before start of the dietary DDC treatment, after 2 weeks of DDC treatment, and after 4 weeks of DDC treatment. Body weights and plasma markers of liver damage (ALT, AST, alkaline phosphatase (ALP) and bilirubin) were measured. DDC treatment was associated with substantial loss of body weight. However, body weight loss was less severe in DDC-treated mice in which the Baat or Slc27a5 gene had been inactivated in the liver (Figure 9A). In addition, liver damage markers not only confirmed that the DDC diet did indeed cause liver pathology, but also demonstrates that inactivation of the Baat or Slc27a5 gene in the liver ameliorates liver pathology in the DDC diet-fed mice (Figure 9 B-D). Since DDC treatment of mice represents an established preclinical model for cholestatic liver disease, these data provide further support for the novel concept that both BAAT and SLC27A5 represent targets for therapy in patients with cholestatic liver diseases or other bile acid-related liver pathologies. * p<0.05 compared to DDC-fed controls using Mann-Whitney U test. EXAMPLE 5: Exemplary inhibitory nucleic acids targeting BAAT The coding sequence (cds) of the human BAAT gene was cloned into the dual reporter vector pMIR-GLO (Promega) using the restriction enzyme sites NheI and SalI, placing it 3’ of the firefly luciferase-encoding gene sequence in the vector. Three siRNA’s were designed to target the nucleotide sequence 976-997 (siRNA_1), 746-771 (siRNA_2) or 603-624 (siRNA_3) of the human BAAT gene, respectively. See Table 2 herein above and Figures 10A and 10B. HEK293A cells were plated at a density of 3 x 10⁴ cells per well in 96-well plates and transfected with 50 ng of pMIR-GLO, containing the human BAAT cds, and 6 pmol of siRNA using Lipofectamine 2000 transfection reagent (Thermofisher Scientific) according to the manufacturer’s protocol. Firefly and Renilla luciferase activities were quantified 48 hours later using the Dual-Luciferase Reporter Assay System (Promega), in which Renilla luciferase activity was used for normalization. Reduced Firefly/Renilla luciferase ratios indicate higher effectivity of the BAAT-targeting siRNA. Based on this assay, siRNA_1, siRNA_2 and siRNA_3 repressed BAAT expression by77.3%, 86.4% and 84.1%, respectively (Figure 10C). *** p<0.001 using Mann-Whitney U test. 5 EXAMPLE 6: Exemplary inhibitory nucleic acids targeting BAAT or SLC27A5. A. Targeting Homo sapiens bile acid-CoA:amino acid N-acyltransferase 10 (BAAT) Transcript variant 1 : NCBI Reference Sequence: NM_001701.4 Ensemble Reference: ENST00000259407.7 BAAT-201 15 Transcript variant 2 : NM_001127610.2 Transcript variant 3 : NM_001374715.1 Table 3: siRNA targeting Homo sapiens bile acid-CoA:amino acid N- acyltransferase (BAAT) 20 seed-duplex RNA oligo sequences stabilty (Tm); target target sequence 21nt guide (5′→3′) position 21nt target + 2nt overhang 21nt passenger (5′→3′) guide passenger UUUAUUGUUCACUAUUAACUC 6.9 485-507 GAGTTAATAGTGAACAATAAAGT -2.3 °C GUUAAUAGUGAACAAUAAAGU °C 1415- AUUUUCUAGGAAUAUCUAGUC 7.1 GACTAGATATTCCTAGAAAATAA 8.2 °C 1437 CUAGAUAUUCCUAGAAAAUAA °C 1554- AGUAUAAGUGAAAUAUCAGGU 6.3 ACCTGATATTTCACTTATACTGC 8.7 °C 1576 CUGAUAUUUCACUUAUACUGC °C Table 4: sgRNA (SpCas9) targeting Homo sapiens bile acid-CoA:amino acid N-acyltransferase (BAAT) Position/ Guide Sequence + PAM (5′→3′) Strand 422 / fw ACCTGGTGTCACACGAATTA AGG 66 / fw CCAGTGCATATCCGAGCTAC AGG 403 / rev ACCTTAATTCGTGTGACACC AGG Table 5: sgRNA (SaCas9) targeting Homo sapiens bile acid-CoA:amino acid N-acyltransferase (BAAT) Position/ Guide Sequence + PAM (5′→3′) Strand 4 / rev CTCACAGGGGTAGCTGTCAA CTGGAT 66 / fw TCCAGTTGACAGCTACCCCT GTGAGT 403 / rev TCAAGCCCACTATAGGGCCA ATGAAT B. Targeting Homo sapiens solute carrier family 27 member 5 (SLC27A5) Transcript variant 1 : NM_012254.3 Transcript variant 2 : NM_001321196.2 Table 6: siRNA targeting Homo sapiens solute carrier family 27 member 5 (SLC27A5) seed-duplex RNA oligo sequences stabilty (Tm); target target sequence 21nt guide (5′→3′) position 21nt target + 2nt overhang 21nt passenger (5′→3′) guide passenger AGGAAGUAGAGAACUUGGGGG 26.4 861-883 CCCCCAAGTTCTCTACTTCCTGC 23.2 °C CCCAAGUUCUCUACUUCCUGC °C 1093- UUGACUAAGCCCAUGUUGCCU 20.3 AGGCAACATGGGCTTAGTCAACT 18.1 °C 1115 GCAACAUGGGCUUAGUCAACU °C 1354- UAAACGUCGCCCGAUUGCCGC 22.2 GCGGCAATCGGGCGACGTTTACT 28.2 °C 1376 GGCAAUCGGGCGACGUUUACU °C Table 7: sgRNA (SpCas9) targeting Homo sapiens solute carrier family 27 member 5 (SLC27A5) 5 Position/ Guide Sequence + PAM (5′→3′) Strand Exon 1174 / fw CCCACATGTTGCGTGCTACT TGG Exon 1154 / rev CCAAGTAGCACGCAACATGT GGG Exon 1155 / rev CCCAAGTAGCACGCAACATG TGG Table 8: sgRNA (SaCas9) targeting Homo sapiens solute carrier family 27 member 5 (SLC27A5) Position/ Guide Sequence + PAM (5′→3′) Strand Exon 1152 / rev CCCAAGTAGCACGCAACATG TGGGAT Exon 1350 / fw CCACCTGGGCCTGAAGATCA GGGGAT Exon 290 / fw AGCCATACCTCCCCTACACC AGGGGT 0

Claims

Claims 1. An inhibitor of bile acid conjugation and/or reconjugation, for use in a method of alleviating symptoms in a subject suffering from a cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH), wherein the inhibitor suppresses or inhibits the expression or activity of the bile acid- CoA:amino acid N-acyltransferase (BAAT) gene or the solute carrier family 27 member 5 (SLC27A5) gene or the gene product thereof.

2. The inhibitor for use according to claim 1, wherein the inhibitor suppresses or inhibits the expression or activity of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or its gene product.

3. The inhibitor for use according to claim 1, wherein the inhibitor suppresses or inhibits the expression or activity of the solute carrier family 27 member 5 (SLC27A5) gene or its gene product.

4. The inhibitor for use according to any one of claims 1-3, wherein the inhibitor is or comprises a peptide, a peptidomimetic, a small molecule inhibitor, an inhibitory (antisense) oligonucleotide, or a polypeptide molecule.

5. The inhibitor for use according to claim 4, wherein the inhibitor is an inhibitory oligonucleotide targeting BAAT or SLC27A5.

6. The inhibitor for use according to claim 5, wherein the inhibitor is selected from the group consisting of an isolated or synthetic antisense RNA or DNA, siRNA or siDNA, DNA/RNA aptamer, miRNA, miRNA mimics, shRNA or DNA and chimeric antisense DNA or RNA, preferably wherein the inhibitor is siRNA.

7. The inhibitor for use according to any one of claims 1-6, for use in a method of alleviating symptoms associated with non-alcoholic steatohepatitis (NASH).

8. The inhibitor for use according to any one of claims 1-6, for use in a method of alleviating symptoms associated with a cholestatic liver disease (CLD).

9. The inhibitor for use according to claim 8, wherein the CLD is selected from the group consisting of Progressive Familial Intrahepatic Cholestasis (PFIC) types, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), obstructive cholestatic liver diseases, biliary atresia and Alagille syndrome.

10. The use of bile acid-CoA:amino acid N-acyltransferase (BAAT) and/or the SLC27A5 gene or their gene product(s), as therapeutic target in a method to reduce or slow down the progression or development of liver damage in a subject suffering from a cholestatic liver disease.

11. A method of stimulating/enhancing bile flow in a subject with cholestatic liver disease, comprising suppressing or inhibiting the expression or activity of the acid-CoA:amino acid N-acyltransferase (BAAT) and/or the SLC27A5 gene or their gene product(s).

12. The use or the method according to claim 10 or 11, wherein said targeting comprises liver-specific targeting of BAAT and/or SLC27A5, preferably in combination with one or more of agent(s) that block intestinal bile acid reabsorption, such as colesevelam or an IBAT inhibitor.

13. The inhibitor for use according to any one of claims 1-9, or the use or method according to any one of claims 10-12, wherein the subject is a human subject, preferably wherein said human subject is an infant.

14. A pharmaceutical composition comprising an inhibitor of the bile acid-CoA:amino acid N-acyltransferase (BAAT) gene or gene product, and a pharmaceutically acceptable carrier, vehicle or diluent.

15. The pharmaceutical composition according to claim 14, wherein the inhibitor is an inhibitory oligonucleotide selected from an isolated or synthetic antisense RNA or DNA, guideRNA (gRNA), siRNA or siDNA, DNA/RNA aptamer, miRNA, miRNA mimics, shRNA or DNA and chimeric antisense DNA or RNA.

16. The pharmaceutical composition according to claim 15, comprising siRNA or a gRNA targeting BAAT, preferably wherein said siRNA or gRNA is conjugated to GalNac or a liver targeting lipid moiety

17. The pharmaceutical composition according to any one of claims 14-16, comprising one or more further inhibitor(s) of intestinal bile acid reuptake and/or inhibitor(s) of hepatic bile acid synthesis, preferably a bile acid sequestrant and/or an IBAT inhibitor and/or an FXR agonist and/or a FGF19 mimetic.

18. The pharmaceutical composition according to any one of claims 14-17, further comprising an inhibitor of the SLC27A5 gene or gene product.

19. A method of treating a disease associated with hepatic accumulation of bile acids in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 14-18.

20. The method according to claim 19,wherein the disease is a cholestatic liver disease (CLD) or non-alcoholic steatohepatitis (NASH), preferably selected from the group consisting of Progressive Familial Intrahepatic Cholestasis (PFIC) types, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), obstructive cholestatic liver diseases, biliary atresia and Alagille syndrome.