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

JOURNAL OF HEPATOLOGY

卷:74

Article

Wei, Guangyan^1,2  Cao, Jingsong³  Huang, Pinzhu¹  An, Ping^1,4  Badlani, Disha¹  Vaid, Kahini A.¹  Zhao, Shuangshuang¹  Wang, David Q-H.⁵  Zhuo, Jenny³  Yin, Ling³  Frassetto, Andrea³  Markel, Arianna^3,6  Presnyak, Vladimir⁷  Gandham, Srujan⁸  Hua, Serenus⁸  Lukacs, Christine³  Finn, Patrick F.³  Giangrande, Paloma H.³  Martini, Paolo G. V.³  Popov, Yury V.¹ 

[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Boston, MA 02115 USA

[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Radiat Oncol, Guangzhou, Peoples R China

[3] Moderna Inc, Rare Dis, Cambridge, MA USA

[4] Wuhan Univ, Renmin Hosp, Div Gastroenterol & Hepatol, Wuhan, Hubei, Peoples R China

[5] Albert Einstein Coll Med, Einstein Mt Sinai Diabet Res Ctr, Marion Bessin Liver Res Ctr, Dept Med & Genet,Div Gastroenterol & Liver Dis, Bronx, NY 10467 USA

[6] Boston Childrens Hosp, Stem Cell Program, Boston, MA USA

[7] Moderna Inc, Computat Engn, Cambridge, MA USA

[8] Moderna Inc, Analyt Dev, Cambridge, MA USA

关键词: Cholangiopathy;    Cholangitis;    Congenital biliary cirrhosis;    Gene therapy;    Liver fibrosis;   

DOI  :  10.1016/j.jhep.2020.12.010

来源: Elsevier

【 摘 要 】

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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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