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Mutant macaque factor IX T262A: a tool for hemophilia B gene therapy studies in macaques. 2010

Akira Ishiwata, and Jun Mimuro, and Hiroaki Mizukami, and Yuji Kashiwakura, and Atsushi Yasumoto, and Asuka Sakata, and Tsukasa Ohmori, and Seiji Madoiwa, and Fumiko Ono, and Midori Shima, and Akira Yoshioka, and Keiya Ozawa, and Yoichi Sakata
Divisions of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi-ken 329-0498, Japan.

BACKGROUND Gene therapy is expected to be the next generation therapy for hemophilia, and a good animal model is required for hemophilia gene therapy preclinical studies. METHODS Taking advantage of the human factor IX (FIX) specificity of monoclonal antibody 3A6, the epitope of which resides in the amino acid polypeptide segment including Ala 262 of human FIX, mutant macaque FIX with an amino acid substitution of Thr 262 to Ala (macaque FIX T262A) was generated and its reactivity to monoclonal antibody 3A6, biological activity and expression in vivo were studied. RESULTS Enzyme-linked immunosorbent assays (ELISAs) and Western blot analyses showed that monoclonal antibody 3A6 bound to human FIX and macaque FIX T262A but not to wild-type macaque FIX. Recombinant macaque FIX T262A exhibited a comparable coagulation activity to wild-type macaque FIX and human FIX. High expression of macaque FIX T262A was achieved in mice by injection of AAV8 vectors carrying the macaque FIX T262A gene and reached levels of up to 31.5microg/mL (1050% of the normal human FIX concentration). Macaque FIX T262A expressed in the liver of mice was as biologically active as that expressed in vitro. In addition, the macaque FIX T262A concentrations determined by a 3A6-based ELISA were not influenced by the presence of normal macaque plasma. CONCLUSIONS The results of the present study suggest that macaque FIX T262A may be processed appropriately in vivo and that the macaque FIX T262A concentration in the macaque circulation can be quantified precisely by a monoclonal antibody 3A6-based ELISA.

UI MeSH Term Description Entries
D008251 Macaca A genus of the subfamily CERCOPITHECINAE, family CERCOPITHECIDAE, consisting of 16 species inhabiting forests of Africa, Asia, and the islands of Borneo, Philippines, and Celebes. Ape, Barbary,Ape, Black,Ape, Celebes,Barbary Ape,Black Ape,Celebes Ape,Macaque,Apes, Barbary,Apes, Black,Apes, Celebes,Barbary Apes,Black Apes,Celebes Apes,Macacas,Macaques
D002836 Hemophilia B A deficiency of blood coagulation factor IX inherited as an X-linked disorder. (Also known as Christmas Disease, after the first patient studied in detail, not the holy day.) Historical and clinical features resemble those in classic hemophilia (HEMOPHILIA A), but patients present with fewer symptoms. Severity of bleeding is usually similar in members of a single family. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. Treatment is similar to that for hemophilia A. (From Cecil Textbook of Medicine, 19th ed, p1008) Christmas Disease,Factor IX Deficiency,Deficiency, Factor IX,F9 Deficiency,Haemophilia B,Hemophilia B Leyden,Hemophilia B(M),Plasma Thromboplastin Component Deficiency,Bs, Hemophilia,Deficiencies, F9,Deficiencies, Factor IX,Deficiency, F9,Disease, Christmas,F9 Deficiencies,Factor IX Deficiencies,Haemophilia Bs,Hemophilia Bs,Hemophilia Bs (M)
D004797 Enzyme-Linked Immunosorbent Assay An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. ELISA,Assay, Enzyme-Linked Immunosorbent,Assays, Enzyme-Linked Immunosorbent,Enzyme Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assays,Immunosorbent Assay, Enzyme-Linked,Immunosorbent Assays, Enzyme-Linked
D005164 Factor IX Storage-stable blood coagulation factor acting in the intrinsic pathway of blood coagulation. Its activated form, IXa, forms a complex with factor VIII and calcium on platelet factor 3 to activate factor X to Xa. Deficiency of factor IX results in HEMOPHILIA B (Christmas Disease). Autoprothrombin II,Christmas Factor,Coagulation Factor IX,Plasma Thromboplastin Component,Blood Coagulation Factor IX,Factor 9,Factor IX Complex,Factor IX Fraction,Factor Nine,Factor IX, Coagulation
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000911 Antibodies, Monoclonal Antibodies produced by a single clone of cells. Monoclonal Antibodies,Monoclonal Antibody,Antibody, Monoclonal
D000939 Epitopes Sites on an antigen that interact with specific antibodies. Antigenic Determinant,Antigenic Determinants,Antigenic Specificity,Epitope,Determinant, Antigenic,Determinants, Antigenic,Specificity, Antigenic
D015316 Genetic Therapy Techniques and strategies which include the use of coding sequences and other conventional or radical means to transform or modify cells for the purpose of treating or reversing disease conditions. Gene Therapy,Somatic Gene Therapy,DNA Therapy,Gene Therapy, Somatic,Genetic Therapy, Gametic,Genetic Therapy, Somatic,Therapy, DNA,Therapy, Gene,Therapy, Somatic Gene,Gametic Genetic Therapies,Gametic Genetic Therapy,Genetic Therapies,Genetic Therapies, Gametic,Genetic Therapies, Somatic,Somatic Genetic Therapies,Somatic Genetic Therapy,Therapies, Gametic Genetic,Therapies, Genetic,Therapies, Somatic Genetic,Therapy, Gametic Genetic,Therapy, Genetic,Therapy, Somatic Genetic
D016297 Mutagenesis, Site-Directed Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion. Mutagenesis, Oligonucleotide-Directed,Mutagenesis, Site-Specific,Oligonucleotide-Directed Mutagenesis,Site-Directed Mutagenesis,Site-Specific Mutagenesis,Mutageneses, Oligonucleotide-Directed,Mutageneses, Site-Directed,Mutageneses, Site-Specific,Mutagenesis, Oligonucleotide Directed,Mutagenesis, Site Directed,Mutagenesis, Site Specific,Oligonucleotide Directed Mutagenesis,Oligonucleotide-Directed Mutageneses,Site Directed Mutagenesis,Site Specific Mutagenesis,Site-Directed Mutageneses,Site-Specific Mutageneses

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