Hemophilia A
Hemophilia is a bleeding disorder caused by a deficiency in one of the blood clotting factors. Hemophilia A accounts for about 80 percent of all hemophilia cases and results from a deficiency in clotting factor VIII. Hemophilia A is a hereditary disorder that affects approximately 1 in 10,000 males. There are approximately 17,000 affected individuals, mostly males, in the Unites States.
RNA Therapy for Hemophilia A
VIRxSYS has tested SMaRT™ technology in hemophilic factor VIII knockout mice. Using different modes of PTM delivery we have generated RNA, protein, activity and phenotypic data showing that we have achieved significant and therapeutic levels of factor VIII repair in this animal model (Nature Medicine 9: 1015-19 2003).
Advantages of SMaRT™ for Hemophilia A Gene Therapy
Following this successful demonstration in RNA repair of the defective Factor VIII gene in mice, VIRxSYS investigators next tried a completely new and innovative approach. Following the successful demonstration of the albumin gene in the liver described above, we used the same strategy with Factor VIII – re-program the albumin pre-mRNA to encode for production of Factor VIII. This has been achieved and was published in early 2009 in Molecular Therapy, the official journal of the American Society of Gene Therapy (Wang et al. Mol Ther.17:343, 2009.).
Transgene regulation: Trans-splicing occurs only in cells that normally express factor VIII. This avoids issues of expressing the Factor VIII protein in an improper cell.
Complete Factor FVIII protein: Trans-splicing generates a complete factor VIII protein that contains a portion of the B-domain, an important component in the release of factor VIII from hepatocytes. It is also produced in the same cell that makes Factor VIII normally. Conventional gene therapy approaches that utilize a vector known as AAV require the use of a B-domain deleted form of the cDNA to achieve efficient packaging. While the shortened form of factor VIII appears to have similar clotting activity compared to the plasma derived full-length protein, several studies suggest that the B-domain may be required for efficient processing and secretion of the protein.