Alpha-1 Antitrypsin for Hereditary Deficiency

DESCRIPTION (provided by applicant): The overall goal of this program is to provide an abundant, cost-effective, biosecure source of human alpha-1 antitrypsin for human therapeutic use by producing recombinant human alpha-1 antitrypsin (rhAAT) in the milk of transgenic goats. Human alpha-1 antitrypsin is currently isolated from donated human plasma, but shifts in the plasma fractionation industry, concerns about cost, and anxiety about blood safety have motivated efforts to produce rhAAT as an alternative source for human therapeutic applications. GTC Biotherapeutics Inc. (GTC-Bio) has developed a recombinant expression technology that uses transgenic dairy animals for the production of important biotherapeutics. Several lines of transgenic goats have been obtained that express rhAAT in their milk at levels of up to 20 g/l, which is adequate to address both hereditary deficiency, the current indication, as well as other potential indications such as cystic fibrosis and acute respiratory distress syndrome (ARDS). In this Phase I SBIR project, we propose to establish proof of principle of the production of rhAAT suitable for augmentation therapy of hereditary deficiency patients by: 1) characterizing the AAT transgene from transgenic founder goats that express rhAAT in their milk to select the best transgenic goat line for the establishment of Master and Working Transgenic Banks and for herd scale-up; 2) characterizing the activity, structure, and carbohydrate composition of the rhAAT protein expressed in the milk of transgenic goats; and 3) determining the half-life of the rhAAT protein in a rat model. Completion of this Phase I project will lead to a Phase II proposal to engage in the large-scale production of a rhAAT protein suitable for pre-clinical and early clinical studies. If this approach is successful, it will permit GTC-Bio to develop a recombinant option for the treatment of AAT hereditary deficiency by intravenous augmentation therapy. Further, it will offer a safe, abundant source of AAT that will be available to explore other modes of delivery of the drug, such as aerosolization, and to engage in clinical studies in cystic fibrosis, asthma, and ARDS.