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Mol Ther ; 26(2): 496-509, 2018 02 07.
Article in English | MEDLINE | ID: mdl-29292164

ABSTRACT

Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients.


Subject(s)
Factor VIII/genetics , Genetic Therapy , Hemophilia A/genetics , Hemophilia A/therapy , Peptide Fragments/genetics , Animals , Apoptosis/genetics , Cell Line , Dependovirus/genetics , Disease Models, Animal , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Gene Expression , Gene Order , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Hemophilia A/blood , Liver/metabolism , Male , Mice , Mice, Transgenic , Peptide Fragments/blood , Primates , Promoter Regions, Genetic
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