Experts ‘cautiously optimistic’ about the prospects of gene and cell-based therapy for hemophilia
The goal of a long-lasting treatment for hemophilia using innovative gene and cell-based strategies remains a feasible objective, as seen from papers presented at three independent meetings last spring. Recent advances were described at the U.S. National Hemophilia Foundation workshop on gene therapy in Philadelphia, the WFH Congress in Vancouver, and the annual meeting of the American Society of Gene Therapy (ASGT).
The best results to date from clinical hemophilia gene transfer have occurred in the Avigen-sponsored trial in the U.S., using a recombinant adeno-associated viral (AAV) vector to deliver factor IX to the liver. (A vector is a method to transfer DNA sequences from one organism to another.)
In one patient studied, a plasma factor IX level of 12% was achieved and therapeutic levels were expressed for a month before returning to baseline levels, accompanied by evidence of liver cell toxicity. Subsequent immunologic analysis in another patient showed that liver damage following vector delivery is most likely due to a host immune response against components of the vector protein coat. In other words, the patient’s immune system recognized the vector from previous virus exposure and attacked it.
Despite this setback, there is still well-founded enthusiasm for the AAV delivery system. Recent studies in hemophilia A dogs show that long-term expression of therapeutic levels of factor VIII can be achieved with this vector, while two upcoming human clinical trials will use AAV delivery in hemophilia B patients.
A study coordinated by Dr. Kathy High in the U.S. intends to use a temporary course of immunosuppression to abolish the host immune response to the vector. A second study involves centres in the U.K. (Drs. Amit Nathwani and Ted Tuddenham) and the U.S. (Dr. Andrew Davidoff). In this second study, researchers are trying to circumvent the host immune response by switching to a vector with a different protein coat (AAV8), which may be less likely to be recognized and attacked. The trials may begin to enroll patients later this year.
There has also been progress with the preclinical application of certain types of retroviral vectors. Retroviral delivery systems have the capacity to insert their clotting factor gene “cargo” into the patient’s chromosomes, and are thus well suited for the modification of stem cells that can then serve as depot sites for clotting factor expression. (Stem cells are cells that retain the ability to become specialized and take the place of cells that have a specific task.)
Encouraging preliminary data has shown that this approach might be feasible using patient blood stem cells, with subsequent re-introduction of the genetically modified cells into the patient for long-term factor delivery. The retroviral strategies will still need to demonstrate a lack of immune activation and, depending upon where the cells have been re-implanted, long-term viability.
As several different strategies for hemophilia gene transfer are explored in pre-clinical studies, the challenge of the host immune response continues to limit long-term success. Evidence suggests that the delivery of clotting factor genes to specific parts of the body, such as the liver, may facilitate the development of immunologic tolerance to the newly expressed clotting factor protein.
Furthermore, recent studies presented at the ASGT meeting indicate that gene transfer approaches using the cell’s own regulatory machinery can limit protein expression to defined cell types, and thus minimize the risk of adverse immune responses such as clotting factor inhibitor development.
Overall, the hemophilia gene transfer community remains cautiously optimistic about future advances towards the goal of long-term correction of the bleeding tendency in hemophilia. The next year will undoubtedly provide new information about the rate and extent of this progress.
Professor David Lillicrap
Queen's University, Kingston, Canada
Hemophilia World, September 2006 issue
Updated September 2006 |
