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

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
    • Publication Information:
      Publication: 2001- : Amsterdam : Elsevier
      Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
    • Subject Terms:
      Gene Deletion* ; Phenotype*; ATP Binding Cassette Transporter, Subfamily B/*deficiency ; Cholestasis, Intrahepatic/*drug therapy ; Cholestasis, Intrahepatic/*genetics ; Liposomes/*chemistry ; Nanoparticle Drug Delivery System/*chemistry ; Nanoparticles/*chemistry ; RNA, Messenger/*administration & dosage; ATP Binding Cassette Transporter, Subfamily B/administration & dosage ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Animals ; Cholestasis, Intrahepatic/metabolism ; Disease Models, Animal ; HEK293 Cells ; Homozygote ; Humans ; Liver/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; RNA, Messenger/genetics ; Transfection ; Treatment Outcome ; ATP-Binding Cassette Sub-Family B Member 4
    • Abstract:
      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.
      Lay Summary: This report describes the development of an innovative mRNA therapy as a potential treatment for PFIC3, a devastating rare paediatric liver disease with no treatment options except liver transplantation. We show that administration of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice.
      Competing Interests: Conflicts of interest JC, JZ, LY, AF, VP, SG, SH, CL, PF, PHG, and PM are employees of, and receive salary, stock, and stock options from, Moderna, Inc. Please refer to the accompanying ICMJE disclosure forms for further details.
      (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
    • Comments:
      Comment in: J Hepatol. 2022 Mar;76(3):749-751. (PMID: 34626730)
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    • Grant Information:
      R01 DK114516 United States DK NIDDK NIH HHS; R01 DK126369 United States DK NIDDK NIH HHS; P30 DK034854 United States DK NIDDK NIH HHS; P30 DK020541 United States DK NIDDK NIH HHS; P60 DK020541 United States DK NIDDK NIH HHS; R01 DK106249 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: Cholangiopathy; Cholangitis; Congenital biliary cirrhosis; Gene therapy; Liver fibrosis
    • Accession Number:
      0 (ATP Binding Cassette Transporter, Subfamily B)
      0 (Lipid Nanoparticles)
      0 (Liposomes)
      0 (Nanoparticle Drug Delivery System)
      0 (RNA, Messenger)
      9EI49ZU76O (multidrug resistance protein 3)
    • Subject Terms:
      Cholestasis, progressive familial intrahepatic 3
    • Publication Date:
      Date Created: 20201219 Date Completed: 20220128 Latest Revision: 20231213
    • Publication Date:
      20240513
    • Accession Number:
      PMC8188846
    • Accession Number:
      10.1016/j.jhep.2020.12.010
    • Accession Number:
      33340584