Winter 1998 - Factor Nine News

Future Impacts of Genetic Engineering on Treatment of Hemophilia

At the recent annual meeting of the National Hemophilia Foundation, Professor Gilbert C. White of the University of North Carolina School of Medicine spoke about how genetic engineering technologies have revolutionized the treatment of hemophilia and will continue to do so in the future. In the past decade, genetic engineering, also known as recombinant DNA technology, has given us synthetic clotting factor concentrates. It has also allowed us to study the defects in the Factor VIII and Factor IX genes that lead to hemophilia A and B, respectively. The protease inhibitors used for the treatment of AIDS were also developed through recombinant technology, and similar approaches are in development for the treatment of hepatitis.

Looking into the future, Professor White spoke about what this remarkable technology might bring us in the next decade, focussing on gene therapy and inhibitors. Gene therapy, as we have discussed before, is a potential “cure” for hemophilia. Literally, gene therapy is using genes and their products to treat disorders. This could involve replacement of an abnormal gene, as in hemophilia, or the introduction of a new gene that might, for instance, stimulate the immune system to attack cancer cells.

The challenge is transferring the new genes into the right cells in a way that they will function properly and not disrupt other genes in the cell. Most current methods result in the genes being introduced into essentially all tissues of the body. However, it is possible that the protein made by the new gene could interfere with the functioning of some tissues where that protein is not normally made. Even in the correct tissue the new gene can disrupt proper cell functioning if it inserts itself onto the cell’s chromosomes in a location that interferes with another gene. Thus the usefulness of gene therapy is highly dependent on the development of safe and efficient methods for accomplishing gene transfer. This is the main focus of current research in gene therapy.

A number of target tissues have been proposed for hemophilia gene therapy. The liver is an obvious choice since that is where Factor IX is normally made, but there are a number of other possibilities. The main requirement is good access to the blood for efficient transfer of Factor IX into the bloodstream. Tissues being considered include muscle tissue, endothelial cells which are the cells that line the blood vessels, and bone marrow which is where new blood cells are constantly being made. Other tissues with good exposure to the blood are selected because they are easy to access for gene transfer. These include skin cells, the cells lining the intestines, and the cells lining the lungs.

Viruses are being used by many researchers to deliver new genes to tissues. Here again, genetic engineering is used to replace viral genes with the new, therapeutic gene. Normally when a virus infects a cell, it inserts its genes into the cell and those genes cause the cell to produce more viruses. With these recombinant viruses, however, the virus instead inserts the therapeutic gene into the cell to cause the cell to produce the gene product, for instance Factor IX.

Professor White described a large number of different viruses that are being studied for this purpose. Another approach called chimeraplasty has the potential to actually repair defective genes rather than replacing them.

The second part of Professor White’s talk concerned inhibitors and the uses of genetic engineering to study their formation. Inhibitors are antibodies that inactivate Factor VIII or Factor IX. Up to about 30% of hemophiliacs develop inhibitors, although this is a much greater problem in hemophilia A than in hemophilia B. The inhibitors neutralize injected clotting factor and thus prevent it from working, a serious problem in hemophilia treatment.

During early development of the immune system before birth, the body essentially catalogs all of its proteins. This information is then used for the rest of its life to determine what proteins are “self” and should be left alone, and what proteins are foreign and should be attacked by the immune system. Since a fetus with hemophilia B does not produce normal Factor IX, Factor IX injected later in life may be seen as a foreign protein. Its own defective Factor IX is what the patient’s body sees as “normal”. The mystery is why all hemophiliacs do not develop inhibitors.

The theories are too complex to describe here in detail, but they probably involve the specific defect in the patient’s Factor IX. Some patients produce no Factor IX, while others produce a defective Factor IX that is either missing parts of the molecule or has parts that are different from the normal molecule. The specific difference between the defective Factor IX molecule and a normal Factor IX molecule may help determine whether the body sees the normal molecule as self or foreign. The immune reaction may also depend on the patient’s HLA type. The HLA type is like a blood type, and is another way the body recognizes what is self and what is foreign. The immune systems of patients with different HLA types may react differently depending on the specific defect in the Factor IX molecule. This is all still very poorly understood, and a great deal of research is currently focussed on the issue.

In only a couple of decades since its development genetic engineering has had a tremendous impact on medicine. It has lead to the development of important new therapies and has become a powerful tool of medical research. It is helping us to better understand how the body works and to use that information to devise better methods to intervene when it does not work properly.

Sharing a Brighter Tomorrow Hemophilia B College and Vocational Scholarships

Genetics Institute will hold its third annual scholarship program for applicants with hemophilia A or B. For 1999-2000, ten $5,000 scholarships and ten $1,000 vocational scholarships are available to eligible candidates. Candidates must either be high school senior, have a graduate equivalency diploma (GED), or currently be enrolled in an accredited junior college, college, university, or vocational program. All applications must be received by March 31, 1999. To receive your scholarship information packets please call 1 800 841-6871.