Hemophilia B is a bleeding disorder resulting from congenital deficiency of coagulation protein Factor IX. Without optimal therapy, patients suffer crippling debilitations, chronic pain, and cognitive impairment. Optimal therapy - frequent dosing with Factor IX to reduce bleeding episode frequency - is currently available to only a small fraction of U.S. patients, largely because of cost and limited supply;80% of the world's hemophilia patients receive no therapy. The long-term goal of this research is development of an abundant, pure, safe, and effective therapy for the global hemophilia patient population using recombinant human coagulation proteins produced in the milk of transgenic pigs. This proposal describes studies that are based upon innovative bioengineering technologies to refine and scale-up production of clinical grade Factor IX, characterize product formulated for intravenous dosage, complete animal studies required for clinical trials, and ultimately develop an oral dosage form to provide optimal therapy for U.S. hemophilia B patients. This approach capitalizes on existing genetically engineered transgenic pigs that synthesize up to 1000 IU/ml (4 g/L) of human Factor IX in milk and preliminary evidence for favorable hemostatic and pharmacokinetic properties of this purified Factor IX in a hemophilia B mouse model. A high probability of success is expected because of the soundness and state of development of the basic research already completed and the breadth and complementarity of the strengths of the team. Dr. J. Cooper of ProGenetics LLC will supply FDA- and USDA-compliant Factor IX milk. At the Univ. Nebraska-Lincoln, Dr. M. Meagher provides expertise in bioprocess engineering and current Good Manufacturing Practices production of recombinant proteins;Drs. W. Velander and K. Van Cott contribute expertise in transgenic animal engineering and characterization of human Factor IX. Dr. M. Manning of Colorado State University brings expertise in the formulation of stabilized liquid and lyophilized proteins for oral and injectable dosing. Dr. S. Abramson of LifeSci Partners has two decades of biopharmaceutical development experience encompassing clinical, technical, and regulatory expertise, including AlphaNine(r)SD (purified plasma-derived Factor IX). Drs. P. Monahan and T. Nichols of UNC-Chapel Hill have unique preclinical experience with hemophilia B mice and dogs that will be used to test the safety and efficacy of the Factor IX products.
