The ABCB4 p.T175A variant as potential modulator of hepatic fibrosis in patients with chronic liver diseases: Looking beyond the cholestatic realm

Krawczyk, Marcin; Rau, Monika; Grünhage, F; Schattenberg, Jörn M.; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Böettler, Tobias; Geier, Andreas; Lammert, Frank

doi:10.1002/hep.29100

Cited by 8 publications

(4 citation statements)

References 4 publications

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“…Recent large-scale populational GWAS study in 2,636 Icelanders have further corroborated significant association of ABCB4 with chronic liver disease [47]. It also appears that the common ABCB4 variant p.T175A, which is not known to result in defective PC translocation, is linked to increased liver stiffness in patients with NAFLD [48]. The role of the ABCB4 variation remains unclear in the development of drug-induced liver injury, although several clinical studies have indicated potential association in cholestatic liver injury induced by antibiotics, chemotherapy drugs, and psychotropic drugs, which might be related to the partial, functional ABCB4 deficit [49,50].…”

Section: Non-activation Of Hepatic Stellate Cells/myofiboblasts and Rmentioning

confidence: 88%

“… 47 It also appears that the common ABCB4 variant p.T175A, which is not known to result in defective PC translocation, is linked to increased liver stiffness in patients with non-alcoholic fatty liver disease. 48 The role of the ABCB4 variation in the development of drug-induced liver injury remains unclear, although several clinical studies have indicated a potential association in cholestatic liver injury induced by antibiotics, chemotherapy drugs, and psychotropic drugs, which might be related to the partial, functional ABCB4 deficit. 49 , 50 These observations call for exploration of therapeutic feasibility of ABCB4 overexpression approaches in experimental models of non-PFIC3 liver diseases where functional deficit of ABCB4 is thought to contribute to disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3

Wei

Cao

Huang

et al. 2021

Journal of Hepatology

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Background & Aims: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation. Methods: We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 ( hABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c. Abcb4 −/− mice. Results: We show that treatment with liver-targeted hABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the hABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4 −/− mice, with rapid and dramatic normalisation of all clinically relevant parameters such as inflammation, ductular reaction, and liver fibrosis. Synthetic mRNA therapy also promoted favourable hepatocyte-driven liver regeneration to restore normal homeostasis, including liver weight, body weight, liver enzymes, and portal vein blood pressure. Conclusions: Our data provide strong preclinical proof-of-concept for hABCB4 mRNA therapy as a potential treatment option for patients with PFIC3.

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Section: Non-activation Of Hepatic Stellate Cells/myofiboblasts and Rmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3

Wei

Cao

Huang

et al. 2021

Journal of Hepatology

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“…The potential effects of a common ABCB4 variation (e.g., rs58238559 ¼ p. T175A) on chronic liver injury stiffness was also noted in a case-control study using transient elastography. 58…”

Section: Progressive Familial Intrahepatic Cholestasis Typementioning

confidence: 99%

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Reichert

2018

Semin Liver Dis

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ATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which “flops” phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency–associated mutations can guide the development of novel genotype–based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.

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“…A wide-spectrum of rare liver diseases is caused by mutations in the ABCB4 gene including progressive familial intrahepatic cholestasis type 3 (PFIC3), low-phospholipid associated cholelithiasis (LPAC) syndrome, and other rare biliary diseases (e.g., primary biliary cirrhosis) [5][6][7][8][9]. Moreover, variants in this transporter could play a role in driving liver fibrosis in patients with chronic liver diseases [10]. PFIC3 patients develop symptoms during late infancy, including severe itching, jaundice, and failure to thrive, and can progress to liver failure during childhood or adulthood.…”

Section: Introductionmentioning

confidence: 99%

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Alsuraih

LaViolette

Lin

et al. 2023

Preprint

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Mutations in the ABCB4 gene lead to a wide-spectrum of rare liver diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3) and low-phospholipid associated cholelithiasis (LPAC) syndrome. PFIC3 patients develop symptoms during late infancy, including severe itching, jaundice, and failure to thrive. The condition may progress to liver failure during childhood or adulthood. This is a highly unmet medical condition where liver transplantation is the only option to correct this disease. Recently, exciting data suggested that restoration of the ABCB4 function via gene replacement could rescue liver phenotypes associated with ABCB4 dysfunction in a pre-clinical PFIC3 mouse model. Here, we used mRNA LNP platform to determine expression and durability of ABCB4 in the liver of wild-type mice. In addition, we generated Abcb4-/- mice to study the efficacy of systemic delivery of ABCB4 mRNA LNP. We observed a robust and durable expression of hABCB4 up to 72 hours post systemic dosing in the liver of wild-type mice. Systemic administration of hABCB4 mRNA achieved a remarkable restoration of phosphatidylcholine levels in bile, a significant decrease in liver stiffness as measured by shear wave elastography, and amelioration of liver histopathology including fibrosis and ductular reaction. We conclude that administration of hABCB4 mRNA LNPs was sufficient to ameliorate fibrosis markers in the PFIC3 mouse model. Our data suggests that gene replacement using mRNA LNP modality could provide an excellent opportunity for patients with biliary diseases.

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The ABCB4 p.T175A variant as potential modulator of hepatic fibrosis in patients with chronic liver diseases: Looking beyond the cholestatic realm

Cited by 8 publications

References 4 publications

Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3

Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

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