The ultimate goal of gene therapy is the replacement of a defective gene sequence with a corrected gene sequence to eliminate disease for the lifetime of the patient.
Hemophilia is caused by mutations in one of the proteins that involved in blood clotting are predominantly Factor VIII or Factor IX.
Hemophilia A and B are X-chromosome linked recessive bleeding disorders which results a deficiency in factor VIII (FVIII) and factor IX (FIX) respectively.
Patients with mild hemophilia will maintain low levels of the clotting factor i.e. 5% – 40% of the normal level in blood. To treat patients with mild hemophilia, gene therapy agents would need to raise the level of Factor VIII in a patient’s blood to atleast 5% from <1% at diagnosis in severely afflicted patients. However, even increases to levels over 1% can result considerable improvement in disease symptoms and quality of life.
Several gene and cell therapy strategies are in different stages of development to treat hemophilia. Although gene therapy studies with a specific vector in animals showed long term expression of the significant clotting factor (Factor VIII or Factor IX).
Approaches using cell therapy for the treatment of hemophilia are in investigated stage in animal models (pre-clinical studies). To express Factor VIII or Factor IX, hematopoietic stem cells can be modified by gene therapy in tissue culture. Transplantation of these stem cells into mouse models has resolved the disease, and efforts are progressing to extend the approach in dog model of hemophilia.
In United States, clinical trial was conducted for hemophilia B in which the therapeutic gene i.e. Factor IX in an adeno-associated viral vector was incorporated into the liver of patients. Even though gene therapy studies in animals with the same vector showed long term expression of the clotting factor but the therapeutic effect in this human trial was short-term but the possibility of genetically corrected liver cells were recognized as foreign and rejected by the healthy immune system in the patients which is similar to the problem faced by patients after organ transplantation.
Similar to the patients with a transplanted organ, patients who receive the gene therapy for hemophilia may 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 are too low to induce an immune response.