Keogh-Stroka, Deborah M.; Keogh, Adrian; Vu, Dung; Fort, Alfredo; Stoffel, Michael Hubert; Kühni, Kathrin; Furer, Cynthia; Banz Wüthrich, Vanessa; Demarmels Biasiutti, Franziska; Lämmle, Bernhard; Candinas, Daniel; Neerman-Arbez, Marguerite (2014). In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes. Journal of thrombosis and haemostasis, 12(11), pp. 1874-1879. Wiley-Blackwell 10.1111/jth.12714
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Stroka, Keogh et al 2014 - In vitro rescue of FGA.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (686kB) | Request a copy |
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.
METHODS AND 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.
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