The research laboratory of Roland Herzog, PhD, seeks to develop gene therapies that result in a lasting cure of the inherited disorder hemophilia. The laboratory also attempts to define the mechanism of immune responses to adeno-associated viral (AAV) vectors and their therapeutic gene products, to define the mechanism of immune responses to coagulation factors, and to develop immune tolerance protocols that prevent rejection of therapy for hemophilia. These immune tolerance protocols include oral tolerance, hepatic gene transfer, and regulatory T cell induction. This interdisciplinary research integrates gene transfer technology, immunology, hematology, virology and animal model work.
Gene Therapy for Hemophilia Targeting the Liver
Hemophilia is a hematological disorder caused by mutations in the X-linked encoding coagulation factor VIII (hemophilia A) or IX (hemophilia B). Hemophilia occurs in 1 in 5,000 births worldwide. In its severe form (<1% coagulation activity), failure of blood clotting causes spontaneous—and potentially life threatening—bleeds into joints and soft tissues. Patients with hemophilia are currently treated with intravenous infusion of factor protein concentrate, which may have to be administered up to 3 times per week to prevent serious internal bleeds. This lifelong treatment is burdensome and expensive. Due to the costs of the protein drugs, treatment is not typically available in underdeveloped nations.
In contrast, gene therapy has the potential to be curative and lasting for many years after a single round of gene transfer, which has now materialized in humans in clinical trials. This was accomplished by hepatic gene transfer using adeno-asscoiated viral (AAV) vectors, an approach that Dr. Herzog helped to pioneer.
The Herzog Lab continues to study and refine this approach with four primary goals: Develop vectors that are superior in gene transfer to human hepatocytes; define the mechanism of the immune response to AAV and ultimately prevent B and T cell responses to the vector; achieve immune tolerance to the therapeutic transgene product (FVIII or FIX); and define the mechanism by which immune tolerance induction is achieved.
A seminal finding in the lab was that hepatic gene transfer with AAV vectors can induce immune tolerance to the transgene product by induction of CD4+CD25+FoxP3+ regulatory T cells (Treg), deletion of effector T cells and direct suppression of memory B cells. MHC II presentation to CD4+ T cells occurs primarily in draining lymph nodes of the liver and requires both macrophages and dendritic cells. Induced Treg distribute systemically, resulting in enforcement of immune tolerance in other organs. Hepatic AAV gene transfer can be used not only to prevent but also reverse immune responses, for example to eliminate formation of pathogenic antibodies and anaphylaxis against FIX.