In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.

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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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Anatomy
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Keogh-Stroka, Deborah M.; Keogh, Adrian; Stoffel, Michael Hubert; Kühni, Kathrin; Furer, Cynthia; Banz Wüthrich, Vanessa; Demarmels Biasiutti, Franziska; Lämmle, Bernhard and Candinas, Daniel

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1538-7836

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Michael Hubert Stoffel

Date Deposited:

12 Feb 2015 16:03

Last Modified:

16 Jul 2018 14:15

Publisher DOI:

10.1111/jth.12714

PubMed ID:

25163824

BORIS DOI:

10.7892/boris.62685

URI:

https://boris.unibe.ch/id/eprint/62685

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