RARE DISEASE
Disorder of bile acid synthesis
Disorder of bile acid synthesis
Disorder of bile acid synthesis
Drug discovery
5
drugs
With orphan designations
Overview
Bile acid synthesis disorders (BASDs) are rare genetic conditions caused by enzyme defects in bile acid production, leading to toxic metabolite accumulation, cholestasis, and progressive liver injury [1][4][9]. Clinical features include neonatal jaundice, fat-soluble vitamin deficiencies, and failure to thrive [1][4]. Diagnosis combines urine mass spectrometry for atypical bile acids and genetic testing [11][16]. Early treatment with oral cholic acid replacement can prevent liver failure [6][20].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
648 drug discovery papers about Disorder of bile acid synthesis, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
648 drug discovery papers about Disorder of bile acid synthesis, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Decoding the gut interactome after severe trauma: from molecular dialogue to integrative treatment strategies.
Severe trauma constitutes not merely a localized injury, but a systemic insult to the host's barrier systems driven by massive hemorrhage, hemorrhagic shock, and the systemic inflammatory response. Rather than being a passive victim of this cascade, the gut is widely considered a critical mediator contributing to the pathogenesis of remote MODS. The concept of the interactome redefines disease outcome as the product of a dynamic and reciprocal dialogue among host immune status, gut microbiota structure and function, and pathogen virulence expression. This framework offers a conceptual shift from the traditional single-pathogen model. Based on the interactome theory, this paper systematically reviews the current understanding of the evolution of intestinal microecology from symbiotic homeostasis to pathobiome after severe trauma. These include intestinal epithelial energy metabolism crisis induced by shock and hypoperfusion, excessive activation of pattern recognition receptors in the context of concurrent DAMPs and PAMPs, loss of mucosal protection associated with aryl hydrocarbon receptor ligand depletion, cytotoxic transformation suggested to be linked to bile acid metabolism disorder, and iatrogenic stress destruction of colonization resistance. On this basis, this paper outlines an integrated treatment strategy grounded in molecular targets. The strategy encompasses metabolic substrate supplementation with short-chain fatty acids and prebiotics, AhR signal reactivation via dietary tryptophan and phytochemicals, pathogenic group clearance and virulence inhibition using multi-targeted traditional Chinese medicine compounds, neuroimmune regulation through acupuncture, and a new clinical pathway combining dietary pre-rehabilitation with dynamic functional omics monitoring. Finally, we argue that future therapeutic strategies may benefit from shifting from pathogen eradication toward restoring host-microbiota symbiosis. This review provides a systematic framework for the precision intervention of post-traumatic gut microecology, spanning from molecular mechanisms to clinical translation.
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2026-06-22 | Bile acids and bile acid modification in health and disease: from novel modifications to therapeutic interventions.
Bile acids (BAs) serve dual roles as lipid-digesting molecules and key signaling mediators in metabolism and immune regulation. This review systematically examines: 1.the molecular mechanisms underlying BA-mediated regulation of glucolipid m5etabolism and energy expenditure; 2.host- and microbiota-driven BA modifications (e.g., 3-acylation); 3. therapeutic targeting of BA signaling pathways (FXR/TGR5). We highlight emerging strategies, including novel BA modifications, microbiota interventions, and BA-targeted therapies, which reshape BA homeostasis and show therapeutic potential for metabolic, digestive, hepatobiliary, and neoplastic diseases. Furthermore, we emphasize the central role of BA modifications in metabolic regulation and their pathological implications. Advances in multi-omics and AI-driven approaches deepen mechanistic insights and accelerate the translation of BA-based interventions into clinical practice. Most of the findings discussed in this review are derived from preclinical studies (in vitro and animal models); clinical translation of bile.
2026-06-11 | Hepatic CREB Binding Protein/E1A Binding Protein p300 Maintain Bile Acid Homeostasis Through Histone Acetylation-Mediated Kruppel-Like Transcription Factor 10-Bile Salt Export Pump Axis.
Disruption of bile acid metabolism contributes to various liver diseases. Although CREB binding protein/E1A binding protein p300 are known regulators of hepatic metabolism, their role in bile acid homeostasis remains elusive. Metabolomic and transcriptomic analyses on liver-specific CREB binding protein/E1A binding protein p300 knockout mice were performed to assess bile acid metabolism. Cleavage Under Targets & Tagmentation sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to investigate the epigenetic mechanisms underlying CREB binding protein/E1A binding protein p300-mediated bile acid regulation. A mouse model of cholestatic liver disease was established to validate the findings from the liver-specific CREB binding protein/E1A binding protein p300 double-knockout mice by administrating a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Liver-specific CREB binding protein/E1A binding protein p300 deletion caused intrahepatic cholestasis due to impaired bile acid efflux, along with elevated plasma bile acid levels. Transcriptomic and metabolomic analyses revealed decreased expression of bile acid synthesis and transport genes, including Abcb11 (encoding BSEP, the bile salt export pump). Mechanistically, CBP/p300 promoted Abcb11 transcription via H3K27 acetylation. In addition, CREB binding protein/E1A binding protein p300 epigenetically regulated the transcription factor Kruppel-like transcription factor 10, which directly activated Abcb11 expression. Loss of CREB binding protein/E1A binding protein p300 reduced H3K27Ac enrichment at both Klf10 and Abcb11 promoters, leading to their downregulation. Overexpression of either Klf10 or Abcb11 in CREB binding protein/E1A binding protein p300-deficient hepatocytes partially rescued bile acid transport defects. Impaired Kruppel-like transcription factor 10-bile salt export pump regulatory axis was also observed in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced model of hepatic cholestasis. Our findings uncover a novel CREB binding protein/E1A binding protein p300-Kruppel-like transcription factor 10-bile salt export pump regulatory axis that orchestrates bile acid transport and highlight its therapeutic potential for cholestatic liver diseases.
2026-06-05 | Ecology and engineering to modify the bile acid output of a defined microbial community.
The bile acid pool, which is synthesized collaboratively by the host and its microbiome, impacts metabolism, immunity, and disease risk. Targeted microbiome interventions could in principle reshape the bile acid pool for therapeutic benefit, but practical strategies remain elusive. In the course of screening a complex defined community for metabolic phenotypes by dropping out individual strains, we observed that several of the single-strain dropout communities had markedly increased deoxycholic and lithocholic acid levels and a larger bile acid pool. In each of these communities, a second strain-Lactobacillus plantarum-had bloomed. The bile salt hydrolase activity of L. plantarum was necessary and sufficient to expand the size of the bile acid pool. An engineered community in which the bsh gene is overexpressed in multiple Lactobacillus strains confers on mice increased levels of secondary bile acid levels and a larger pool size. By overexpressing a different pair of bile acid metabolic genes in multiple strains of Lactobacillus-7α- and 7β-hydroxysteroid dehydrogenase-we changed the composition of the bile acid pool, enlarging it and redirecting it toward ursodeoxycholic acid. Together, these results demonstrate that fine details of the microbiome's strain composition can have a substantial effect on bile acid metabolism, and that rational manipulation of the microbiome can alter the size and composition of the bile acid pool.
2026-08-13 | Decoding the gut interactome after severe trauma: from molecular dialogue to integrative treatment strategies.
Severe trauma constitutes not merely a localized injury, but a systemic insult to the host's barrier systems driven by massive hemorrhage, hemorrhagic shock, and the systemic inflammatory response. Rather than being a passive victim of this cascade, the gut is widely considered a critical mediator contributing to the pathogenesis of remote MODS. The concept of the interactome redefines disease outcome as the product of a dynamic and reciprocal dialogue among host immune status, gut microbiota structure and function, and pathogen virulence expression. This framework offers a conceptual shift from the traditional single-pathogen model. Based on the interactome theory, this paper systematically reviews the current understanding of the evolution of intestinal microecology from symbiotic homeostasis to pathobiome after severe trauma. These include intestinal epithelial energy metabolism crisis induced by shock and hypoperfusion, excessive activation of pattern recognition receptors in the context of concurrent DAMPs and PAMPs, loss of mucosal protection associated with aryl hydrocarbon receptor ligand depletion, cytotoxic transformation suggested to be linked to bile acid metabolism disorder, and iatrogenic stress destruction of colonization resistance. On this basis, this paper outlines an integrated treatment strategy grounded in molecular targets. The strategy encompasses metabolic substrate supplementation with short-chain fatty acids and prebiotics, AhR signal reactivation via dietary tryptophan and phytochemicals, pathogenic group clearance and virulence inhibition using multi-targeted traditional Chinese medicine compounds, neuroimmune regulation through acupuncture, and a new clinical pathway combining dietary pre-rehabilitation with dynamic functional omics monitoring. Finally, we argue that future therapeutic strategies may benefit from shifting from pathogen eradication toward restoring host-microbiota symbiosis. This review provides a systematic framework for the precision intervention of post-traumatic gut microecology, spanning from molecular mechanisms to clinical translation.
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2026-06-22 | Bile acids and bile acid modification in health and disease: from novel modifications to therapeutic interventions.
Bile acids (BAs) serve dual roles as lipid-digesting molecules and key signaling mediators in metabolism and immune regulation. This review systematically examines: 1.the molecular mechanisms underlying BA-mediated regulation of glucolipid m5etabolism and energy expenditure; 2.host- and microbiota-driven BA modifications (e.g., 3-acylation); 3. therapeutic targeting of BA signaling pathways (FXR/TGR5). We highlight emerging strategies, including novel BA modifications, microbiota interventions, and BA-targeted therapies, which reshape BA homeostasis and show therapeutic potential for metabolic, digestive, hepatobiliary, and neoplastic diseases. Furthermore, we emphasize the central role of BA modifications in metabolic regulation and their pathological implications. Advances in multi-omics and AI-driven approaches deepen mechanistic insights and accelerate the translation of BA-based interventions into clinical practice. Most of the findings discussed in this review are derived from preclinical studies (in vitro and animal models); clinical translation of bile.
2026-06-11 | Hepatic CREB Binding Protein/E1A Binding Protein p300 Maintain Bile Acid Homeostasis Through Histone Acetylation-Mediated Kruppel-Like Transcription Factor 10-Bile Salt Export Pump Axis.
Disruption of bile acid metabolism contributes to various liver diseases. Although CREB binding protein/E1A binding protein p300 are known regulators of hepatic metabolism, their role in bile acid homeostasis remains elusive. Metabolomic and transcriptomic analyses on liver-specific CREB binding protein/E1A binding protein p300 knockout mice were performed to assess bile acid metabolism. Cleavage Under Targets & Tagmentation sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to investigate the epigenetic mechanisms underlying CREB binding protein/E1A binding protein p300-mediated bile acid regulation. A mouse model of cholestatic liver disease was established to validate the findings from the liver-specific CREB binding protein/E1A binding protein p300 double-knockout mice by administrating a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Liver-specific CREB binding protein/E1A binding protein p300 deletion caused intrahepatic cholestasis due to impaired bile acid efflux, along with elevated plasma bile acid levels. Transcriptomic and metabolomic analyses revealed decreased expression of bile acid synthesis and transport genes, including Abcb11 (encoding BSEP, the bile salt export pump). Mechanistically, CBP/p300 promoted Abcb11 transcription via H3K27 acetylation. In addition, CREB binding protein/E1A binding protein p300 epigenetically regulated the transcription factor Kruppel-like transcription factor 10, which directly activated Abcb11 expression. Loss of CREB binding protein/E1A binding protein p300 reduced H3K27Ac enrichment at both Klf10 and Abcb11 promoters, leading to their downregulation. Overexpression of either Klf10 or Abcb11 in CREB binding protein/E1A binding protein p300-deficient hepatocytes partially rescued bile acid transport defects. Impaired Kruppel-like transcription factor 10-bile salt export pump regulatory axis was also observed in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced model of hepatic cholestasis. Our findings uncover a novel CREB binding protein/E1A binding protein p300-Kruppel-like transcription factor 10-bile salt export pump regulatory axis that orchestrates bile acid transport and highlight its therapeutic potential for cholestatic liver diseases.
2026-06-05 | Ecology and engineering to modify the bile acid output of a defined microbial community.
The bile acid pool, which is synthesized collaboratively by the host and its microbiome, impacts metabolism, immunity, and disease risk. Targeted microbiome interventions could in principle reshape the bile acid pool for therapeutic benefit, but practical strategies remain elusive. In the course of screening a complex defined community for metabolic phenotypes by dropping out individual strains, we observed that several of the single-strain dropout communities had markedly increased deoxycholic and lithocholic acid levels and a larger bile acid pool. In each of these communities, a second strain-Lactobacillus plantarum-had bloomed. The bile salt hydrolase activity of L. plantarum was necessary and sufficient to expand the size of the bile acid pool. An engineered community in which the bsh gene is overexpressed in multiple Lactobacillus strains confers on mice increased levels of secondary bile acid levels and a larger pool size. By overexpressing a different pair of bile acid metabolic genes in multiple strains of Lactobacillus-7α- and 7β-hydroxysteroid dehydrogenase-we changed the composition of the bile acid pool, enlarging it and redirecting it toward ursodeoxycholic acid. Together, these results demonstrate that fine details of the microbiome's strain composition can have a substantial effect on bile acid metabolism, and that rational manipulation of the microbiome can alter the size and composition of the bile acid pool.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Disorder of bile acid synthesis, including 2 approved therapies.
5 orphan drug designations for Disorder of bile acid synthesis, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector serotype 3B encoding human CYP27A1 | gene therapies | FDA | 2024-11-26 | — | Vivet Therapeutics SAS |
Adeno-associated viral vector serotype 3B encoding human CYP27A1 | gene therapies | EMA | 2024-08-21 | — | Vivet Therapeutics |
Chenodeoxycholic acid [Chenodeoxycholic acid Leadiant] | small molecules | EMA | 2014-12-16 | 2017-04-12 | Leadiant Biosciences Ireland Limited |
cholic acid [Cholbam] | small molecules | FDA | 2003-07-18 | 2015-03-17 | Mirum Pharmaceuticals, Inc. |
Cholic acid [Orphacol] | small molecules | EMA | 2002-12-18 | — | Theravia |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.