title: In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.
abstract: BACKGROUND
  Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality.
  
  
  OBJECTIVE
  To explore a targeted gene therapy approach for patients with congenital afibrinogenemia.
  
  
  RESULTS
  At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro.
  
  
  CONCLUSIONS
  Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.
authors.affiliation: Clinic for Visceral Surgery and Medicine, Department of Clinical Research, Bern University Hospital, University of Bern, Bern, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Stroka
authors.forename: A
authors.initials: A
authors.lastname: Keogh
authors.forename: D
authors.initials: D
authors.lastname: Vu
authors.forename: A
authors.initials: A
authors.lastname: Fort
authors.forename: M H
authors.initials: MH
authors.lastname: Stoffel
authors.forename: K
authors.initials: K
authors.lastname: Kühni-Boghenbor
authors.forename: C
authors.initials: C
authors.lastname: Furer
authors.forename: V
authors.initials: V
authors.lastname: Banz
authors.forename: F
authors.initials: F
authors.lastname: Demarmels Biasiutti
authors.forename: B
authors.initials: B
authors.lastname: Lämmle
authors.forename: D
authors.initials: D
authors.lastname: Candinas
authors.forename: M
authors.initials: M
authors.lastname: Neerman-Arbez
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D002478:Cells, Cultured; D005340:Fibrinogen / Q000096:biosynthesis / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D016031:Liver Transplantation; D008297:Male; D010641:Phenotype; D014161:Transduction, Genetic
chemical_list: C464794:fibrinogen Aalpha; D005340:Fibrinogen
keywords: congenital afibrinogenemia; fibrinogen Aalpha; genetic therapy; lentivirus; liver transplantation