Hemophilia is a family of clotting disorders. Most patients born with hemophilia are not able to form blood clots efficiently. Any modest injury can trigger excessive bleeding that can endanger life. Patients with severe hemophilia experience life-threatening spontaneous bleeds, unrelated to trauma. Some patients have a mild form of the disease in which a minor injury is not critical, but major trauma, such as car accidents and surgery, pose a significant risk.
Hemophilia is caused by mutations in one of the proteins involved in blood clotting (predominantly Factor VIII or Factor IX). Most patients, roughly 85%, have Hemophilia A and produce too little or no Factor VIII. Factor VIII is a relatively large protein and mutations occur as large deletions (6%), point mutations (43%), or as inversions in which part of the DNA is flipped backwards (intron 22A, intron 1). Patients with Hemophilia B have a defect in their Factor IX gene, such as deletions of variable length or point mutations. Patients with mild hemophilia maintain low levels of the clotting factor (5%-40% of the normal level in blood).
To treat patents with mild hemophilia, gene therapy agents would need to raise the level of Factor VIII in a patent’s blood from <1% at diagnosis in severely afflicted patients to at least 5%. However, even increases to levels over 1% can result in significant improvement in disease symptoms and quality of life.
Currently, patients with severe hemophilia can be administered recombinant, or artificial, clotting factor at defined intervals as a preventative measure. In mild cases, the patients are usually administered the recombinant clotting factor only when needed, such as before surgery.
Several gene and cell therapy strategies are in various stages of development to treat hemophilia. Although gene therapy studies with a specific vector in animals showed long term expression of the relevant clotting factor (Factor VIII or Factor IX), the therapeutic effect in a subsequent human trial was only temporary.
Approaches using cell therapy for the treatment of hemophilia are being investigated in animal models (pre-clinical studies). For example, genetic modification of liver, muscle or blood vessel cells, using viral or non-viral vectors (delivery vehicles for genetic material), are at advanced stages of development. Alternatively, hematopoietic stem cells can be modified by gene therapy in tissue culture to express Factor VIII or Factor IX. Transplantation of these cells into mouse models has resolved the disease, and efforts are underway to extend the approach to the dog model of hemophilia.
In a clinical trial for hemophilia B conducted in the United States, the therapeutic gene (Factor IX) in an adeno-associated viral vector was introduced into the liver of patients. At the highest dose tested, therapeutic levels of the clotting factor were observed in the circulation. Although gene therapy studies with the same vector in animals showed long term expression of the clotting factor, the therapeutic effect in this human trial was short-term. This raised the possibility that the genetically corrected liver cells were recognized as foreign and rejected by the healthy immune system in the patients. This is similar to the problem faced by patients after organ transplantation. Similar to patients with a transplanted organ, patients who receive the gene therapy for hemophilia might benefit from the therapy with temporary immune-suppression or use of a more efficient vector that can produce therapeutic levels of clotting factor at vector doses too low to induce an immune response. Both of these approaches are being tested in two phase I/II clinical trials investigating gene therapy for hemophilia B (factor IX). These trials are open to patient recruitment.
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