Genotype and Adeno-Associated Virus (AAV) Immune Status of Patients with Inherited Blood Diseases (Haemophilia A and B)

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The current method of treating patients with bleeding disorders such as haemophilia A and haemophilia B is by injection of recombinant factor VIII or IX, respectively. Even though there is evidence that prophylactic (continuous) injection of factor prevents long-term complications of the disease, cost is prohibitive. The cost for “on-demand” treatment is approximately $100,000, or more, per year for many adults. Some patients form “inhibitors” (neutralizing antibodies against coagulation factor) which increases the amount of factor needed for treatment, and the associated expense. In view of the cost, inconvenience of injections and the potential for inhibitor formation, effective alternative therapies would be welcome by hemophilic patients. One research approach for haematological diseases involves gene transfer. A research effort towards clinical gene transfer for haemophilia, including Professor John Rasko at RPAH, has focused on viral vector delivery systems based on the adeno-associated virus (AAV). Clinical trials over the past decade have demonstrated the utility of AAV vectors for the delivery of normal factor transgenes to muscle and liver. However, immune responses against AAV capsid (the viral vector “coat”) have prematurely terminated factor expression, most likely by immunologically “clearing” vector-transduced hepatocytes. Initial data indicates that approximately 50% of the haemophilia patient population has pre-existing immunity to AAV, as measured by serum antibodies. Clinical studies incorporating immune modulation have been approved, but there is a need to know the AAV immune status of a number of patients, prior to proposing the research study to patients. Therefore, this study intends to screen a number of patients with haemophilia A and B in order to determine their immune system response to AAV, and the genotype of their disease-causing mutation. Depending on the results of these tests, participants may be offered the opportunity to participate in interventional gene therapy trials for their particular disease.

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