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A novel gene therapy in hemophilia A mouse model by using lipid‐coated Fe 3 O 4 nanoparticles
Author(s) -
Chen YenTing,
Tsai TungChou,
Lai PingShan,
Chen ChuanMu
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.984.2
Subject(s) - genetic enhancement , microbiology and biotechnology , coagulopathy , medicine , in vivo , complementary dna , chemistry , pharmacology , gene , virology , biology , biochemistry
Hemophilia A is a bleeding disorder disease caused by missing or defective coagulation factor VIII (FVIII), a clotting protein. It's a X‐linked recessive genetic disease, mainly due to gene mutation. Magnetic nanoparticles have been used for various biomedical applications, including tumor‐targeting drug carriers, magnetic resonance imaging etc., but was rarely utilized in the field of inherited disease. Dipalmitoylphosphatidylcholine (DPPC) formulate with iron oxide nanoparticles is concerned as a potential material in biomedical therapy with highly biocompatible. The aim of this research is to establish a non‐viral gene therapy approach to cure hemophilia A. In this study, B6;129S‐ F8 tm1Kaz /J knockout mice were used as the animal model which mimic sever hemophilia A patients. The biocompatible material‐ IO@DPPC (DPPC‐Fe 3 O 4 ) was used as a DNA carrier to bring human B‐domain deleted FVIII cDNA (10 μg/mice) into hemophilia A mice by tail vein injection. C57BL/6 mice were used as a normal control and untreated hemophilia A mice as a negative control. Activated partial thromboplastin time results revealed that the blood clotting activity significantly improved in the treatment group when compared to negative control (P<0.05). Furthermore, approximately 75% of IO@DPPC and the FVIII ‐ eGFP plasmids entered the hepatocyte nuclear and expressed green fluorescent protein. Moreover, this therapy did not cause any liver injury from the histology examination in the safety test. In this research, injecting 10 μg/mice of FVIII ‐ eGFP plasmids showed a promising therapeutic effects on hemophilia A mice, but the therapeutic levels only maintain until two weeks. To prolong the therapeutic efficacy for more than 6 months, we intend to use higher dosage of FVIII ‐ eGFP plasmids (20 to 50 μg/mice). Taken together, we have successfully improved the bleeding disorder in hemophilia A knockout mice, that provide a potential novel gene therapy approach in the clinical use of hemophilia A patients.