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December 12th, 2003 Octagene Developing Cost Efficient Oral Therapy for People with Haemophilia A  Research activities at Octagene may lead to a gene therapy approach for the treatment of blood clotting disorders, such as haemophilia A. The research focuses on the development of a gene transfer system which would allow for effective oral treatment of haemophilia A, as opposed to the current treatment method of injections of factor VIII. Haemophilia A is a sex-linked bleeding disorder caused by deficiency of coagulation factor FVIII. In the absence of FVIII, patients suffer from frequent spontaneous bleeding.Gene therapy holds great promise for many diseases and disorders. In general, it involves the delivery of recombinant genes or transgenes into somatic cells to replace proteins with a genetic defect or to interfere with the pathological process of an illness. The non-viral gene delivery system described here reveals potential for a non-invasive, cost efficient oral therapy of genetically based disorders. Octagene’s non-viral gene delivery system utilizes a progesterone-progesterone receptor-dependant non invasive oral approach. The system consists of three components, the so called gene transfer cocktail: A DNA vector carrying the human B domain deleted factor VIII (BDDhFVIII) cDNA as transgene under the control of the cytomegalovirus (CMV) promotor and several progesterone-responsive-elements (PRE), the human progesterone receptor protein (hPRA) and micronized progesterone in an oily matrix (Figure 1). Progesterone is thought to support the cellular uptake of the gene therapy cocktail with hPRA protein and enhance the intracellular delivery of the vector DNA to the cell nucleus (Figure 2). This follows the concept that within the cell the DNA-hPRA complex is transported to the nucleus following the physiological steroid transduction pathway. In pilot studies the gene transfer cocktail was administered to FVIII knock-out mice via pharyngeal tube ingestion one time per day for a period of nine days. Blood was withdrawn from the animals each day and coagulation time was measured using the one-stage activated partial thromboplastin time (aPTT) assay. Organs were taken at the end of the treatment, at day 9, for PCR analysis. The BDDhFVIII containing plasmid was detected in all organs. There was a clear reduction in coagulation time in treated FVIII k.o. mice, indicating a therapeutic effect. Further animal in vitro studies will be made to optimize the mode of action of DNA transfer following the oral non-invasive administration. Once the treatment effect is optimized, clinical trials may begin. Haemophilia patients with the severe form of the disease, possessing very little or no factor VIII naturally, receive injections up to 3 times a week for prophylaxis. This non-invasive oral approach from Octagene may offer patients a less painful, less time-consuming, cost effective, and easy solution for acquiring the coagulation factor they lack, thereby enhancing their quality of life dramatically.  Figure 1: The Octagene Gene Transfer System consists of three major components: (1) The DNA-vector, containing several progesterone responsive elements (PRE, blue box) in its backbone. (2) The recombinant human progesterone receptor type A (hPRA); (3) Progesterone in an oily emulsion. In our current approach we are attempting a therapy for haemophilia A, using the BDDhFVIII as therapeutic gene in our transfer system.  Figure 2: Our current concept is that the presence of the steroid hormone progesterone facilitates the transfer of the DNA-hPRA complex into the cell. We believe that within the cell the hormone receptor is targeted to the nucleus (green circle) due to its containing nuclear localization sequence, resulting in a translocation of the bound vector DNA respectively. In our current approach we are attempting a therapy of haemophilia A, using BDDhFVIII as therapeutic gene. OCTAGENE GmbH Biomedical Laboratories is a product-oriented R&D company specializing in the development of new treatments against haemophilia. Our main purpose is to generate and commercialise alternatives to the customary substitution therapy. The production of recombinant clotting factors and gene therapy is the main focus of our research activities. Our expertise lies in several key technologies of modern molecular biology. We have strong competence in the field of protein chemistry, viral and non-viral gene transfer methods using techniques of biochemistry, molecular biology and cell biology. Octapharma thanks Gabi Seigert from Octagene for contributing this story. For more information visit the Octagene website: www.octagene.com (Please note that clicking on this link will take you outside of the Octapharma web site) © Octapharma AG, 2003 |