A MicroRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia a

Hideto Matsui, Carol Hegadorn, Margareth Ozelo, Erin Burnett, Angie Tuttle, Andrea Labelle, Paul B. McCray, Luigi Naldini, Brian Brown, Christine Hough, David Lillicrap

Research output: Contribution to journalArticle

Abstract

The objective to use gene therapy to provide sustained, therapeutic levels of factor VIII (FVIII) for hemophilia A is compromised by the emergence of inhibitory antibodies that prevent FVIII from performing its essential function as a cofactor for factor IX (FIX). FVIII appears to be more immunogenic than FIX and an immune response is associated more frequently with FVIII than FIX gene therapy strategies. We have evaluated a modified lentiviral delivery strategy that facilitates liver-restricted transgene expression and prevents off-target expression in hematopoietic cells by incorporating microRNA (miRNA) target sequences. In contrast to outcomes using this strategy to deliver FIX, this modified delivery strategy was in and of itself insufficient to prevent an anti-FVIII immune response in treated hemophilia A mice. However, pseudotyping the lentivirus with the GP64 envelope glycoprotein, in conjunction with a liver-restricted promoter and a miRNA-regulated FVIII transgene resulted in sustained, therapeutic levels of FVIII. These modifications to the lentiviral delivery system effectively restricted FVIII transgene expression to the liver. Plasma levels of FVIII could be increased to around 9% that of normal levels when macrophages were depleted prior to treating the hemophilia A mice with the modified lentiviral FVIII delivery system.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
JournalMolecular Therapy
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

Factor VII
Factor VIII
Hemophilia A
MicroRNAs
Factor IX
Transgenes
Genetic Therapy
Liver
Lentivirus
Glycoproteins
Macrophages

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Matsui, H., Hegadorn, C., Ozelo, M., Burnett, E., Tuttle, A., Labelle, A., ... Lillicrap, D. (2011). A MicroRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia a. Molecular Therapy, 19(4), 723-730. https://doi.org/10.1038/mt.2010.290

A MicroRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia a. / Matsui, Hideto; Hegadorn, Carol; Ozelo, Margareth; Burnett, Erin; Tuttle, Angie; Labelle, Andrea; McCray, Paul B.; Naldini, Luigi; Brown, Brian; Hough, Christine; Lillicrap, David.

In: Molecular Therapy, Vol. 19, No. 4, 04.2011, p. 723-730.

Research output: Contribution to journalArticle

Matsui, H, Hegadorn, C, Ozelo, M, Burnett, E, Tuttle, A, Labelle, A, McCray, PB, Naldini, L, Brown, B, Hough, C & Lillicrap, D 2011, 'A MicroRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia a', Molecular Therapy, vol. 19, no. 4, pp. 723-730. https://doi.org/10.1038/mt.2010.290
Matsui, Hideto ; Hegadorn, Carol ; Ozelo, Margareth ; Burnett, Erin ; Tuttle, Angie ; Labelle, Andrea ; McCray, Paul B. ; Naldini, Luigi ; Brown, Brian ; Hough, Christine ; Lillicrap, David. / A MicroRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia a. In: Molecular Therapy. 2011 ; Vol. 19, No. 4. pp. 723-730.
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