In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes. (1st October 2014)

• Record Type: Journal Article
• Authors: Stroka, D.; Keogh, A.; Vu, D.; Fort, A.; Stoffel, M. H.; Kühni‐Boghenbor, K.; Furer, C.; Banz, V.; Demarmels Biasiutti, F.; Lämmle, B.; Candinas, D.; Neerman‐Arbez, M.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 11(2014:Nov.)
• Page Start: 1874
• Page End: 1879
• Publication Date: 2014-10-01
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12714
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12714-abs-0001"> <title>Summary</title> <sec id="jth12714-sec-0001" sec-type="section"> <title>Background</title> <p>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 <italic>FGA</italic> 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.</p> </sec> <sec id="jth12714-sec-0002" sec-type="section"> <title>Objective</title> <p>To explore a targeted gene therapy approach for patients with congenital afibrinogenemia.</p> </sec> <sec id="jth12714-sec-0003" sec-type="section"> <title>Methods and Results</title> <p>At the time of transplant, the patient's <italic>FGA</italic>‐deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα‐chain. <italic>FGA</italic>‐transduced hepatocytes produced fully functional fibrinogen <italic>in vitro</italic>.</p> </sec> <sec id="jth12714-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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 <italic>FGA</italic> deletion can be genetically modified to restore Aα‐chain protein expression and secrete a functional fibrinogen hexamer.</p> </sec> </abstract>