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

We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human Progressive familial intrahepatic cholestasis 3 as a result of homozygous disruption of the Abcb4 gene in fibrosissusceptible BALB/c.Abcb4-/- mice

Guangyan Wei; Jingsong Cao; Pinzhu Huang; Ping An; Disha Badlani; Kahini A. Vaid; Shuangshuang Zhao; David Q-H. Wang; Jenny Zhuo; Ling Yin; Andrea Frassetto; Arianna Markel; Vladimir Presnyak; Srujan Gandham; Serenus Hua; Christine Lukacs; Patrick F. Finn; Paloma H. Giangrande; Paolo G.V. Martini; Yury V. Popov

2020

Scholarcy highlights

  • To test whether these constructs resulted in fulllength human or mouse ABCB4 protein translation, protein expression was determined using human or mouse ABCB4 specific antibodies in HEK293 cells transiently transfected with the hABCB4WT or mABCB4WT mRNAs
  • We focused on human ATP-binding cassette 4 mRNA as we aimed to develop the human version as a potential therapy for Progressive familial intrahepatic cholestasis 3
  • 0.0061, respectively, Fig. 4E and F). These results suggest that rapid progression of congenital biliary-type fibrosis was completely halted in BALB/c.Abcb4-/- mice by repeated delivery of ABCB4v6 mRNA-lipid nanoparticles
  • Considering that mRNA therapy can be used to rescue the genetic deficiency via introducing the normal protein for enhancing the expression of specific proteins via systemic administration, an approach that is being currently tested in multiple mRNA-based clinical cancer trials, we hypothesised that it could be applied to therapeutically re-express functional ABCB4 protein in the liver
  • As there was no significant difference between PBS-treated and eGFP mRNALNP-treated groups in any studied parameters, the PBStreated group was not included in subsequent analyses
  • Our recent studies into genetic susceptibility of inbred mouse strains to fibrosis showed that mild disease in original FVB.Abcb4-/- was as a result of its genetic background resistance to fibrosis; transfer of the mutation onto a fibrosis-susceptible background resulted in severe, early-onset portal hypertension and fibrosis progressing at an over 3-fold faster rate and reaching end-stage disease around 7 months of age in BALB/c.Abcb4-/mice
  • Abbreviations AAV, adeno-associated virus; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ERT, enzyme replacement therapy; hABCB4, human ATP-binding cassette 4; HSCs, hepatic stellate cells; IHC, immunohistochemistry; IR, Infrared; LNPs, lipid nanoparticles; PC, phosphatidylcholine; Progressive familial intrahepatic cholestasis 3, progressive familial intrahepatic cholestasis type 3; Portal venous pressure, portal venous pressure; quantitative reverse transcription-PCR, quantitative reverse transcription PCR; TBIL, total bilirubin; Ursodeoxycholic acid, ursodeoxycholic acid

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