We are developing a ZFN-mediated genome editing approach to hemophilia A and B using our proprietary In Vivo Protein Replacement Platform (IVPRP). These programs are currently in preclinical development.
Hemophilia, a rare bleeding disorder in which the blood does not clot normally, is an example of a monogenic disease (a disease that is caused by a genetic defect in a single gene). There are several types of hemophilia caused by mutations in genes that encode factors which help the blood clot and stop bleeding when blood vessels are injured. Individuals with hemophilia experience bleeding episodes after injuries and spontaneous bleeding episodes that often lead to joint disease such as arthritis. The most prevalent form of the disease, hemophilia A, is caused by a defect in clotting Factor VIII, while defects in clotting Factor IX lead to hemophilia B. The most severe forms of hemophilia affect males.
According to the National Hemophilia Foundation and the World Federation of Hemophilia, hemophilia A occurs in about one in every 5,000 male births in the US with approximately 16,000 males currently affected in the US, and hemophilia B in about 1 in every 25,000 male births with approximately 4,000 males currently affected. The standard treatment for individuals with hemophilia is replacement of the defective clotting factor with regular infusion of recombinant clotting factors or plasma concentrates. These therapies are expensive, carry the risk of transmission of blood-borne diseases such as hepatitis and other viral infections and sometimes stimulate the body to produce antibodies against the factors that inhibit the benefits of treatment. In these situations, other clotting factors such as Factor VII and X may be used to treat patients. People with severe forms of the disease may need ongoing, preventive infusions.
Sangamo’s Therapeutic Approach
Using our ZFN technology we are pursuing two approaches in the development of these therapeutics: addition of a new correct copy of the Factor VIII or IX gene into a safe-harbor site, the albumin gene or locus, using our In Vivo Protein Replacement Platform (IVPRP), and correction of the disease-causing mutation in the endogenous copy of the Factor VIII or IX gene.
We have published data demonstrating functional correction of the human factor IX gene in the liver by direct intravenous delivery of AAV encoding ZFNs in a mouse model of the disease (Nature 475, 217–221, 14 July 2011). Preclinical studies of our IVPRP approach, have demonstrated that therapeutic levels of Factor IX could be generated in a dose-dependent manner in non-human primates (NHPs). There were no significant alterations in circulating albumin levels. Studies in mice also demonstrated stable Factor IX production for over 1 year. The IVPRP is designed to be a broadly applicable strategy for gene replacement that will provide a permanent correction for the lifetime of the patient and would reduce or eliminate the need for chronic infusions of replacement proteins or clotting factor products.