Spring 1996 - Factor Nine News

Many of the companies investing in this technology see their goal as the development of general gene therapy techniques that can be used to treat a variety of diseases. Hemophilia B will probably be one of the first diseases to be successfully treated. This is not only because of the need for such treatment, but also because it is a relatively simple, well-understood disease that is being used as a model to develop techniques to treat more complex diseases. Although many different gene therapy methods are being investigated, they all fact two common obstacles: getting enough protein produced and keeping up that production for extended periods of time. One advantage with factor IX is that the amount needed to markedly decrease the severity of the disease is not large. A factor IX level only a few percent of normal gives the blood the ability to clot normally under most circumstances. Thus the production of factor IX does not need to be regulated very precisely. In addition, it does not seen to be important which cells produce the factor IX as long as it can get into the bloodstream. The factor IX molecule has some features that are not common in most proteins and because of this it was once feared that only certain types of cells could produce it accurately. However, it has now been shown that many different types of cells can produce active factor IX.

Genes are the DNA molecules that tell the body’s cells how to make proteins such as factor IX.

In hemophilia B patients the body’s genes for factor IX are defective so the cells either make factor IX molecules that do not work properly, or they make no factor IX at all. Gene therapy would insert correct factor IX genes into the body by one of two basic methods. An in vivo approach introduces new genes directly into the body under condition which allow the genes to be taken up by various cells. Alternatively, an ex vivo approach introduces the new genes into cells in the laboratory, and those cells are then introduced into the body. There are advantages and disadvantages to both methods.

The in vivo method is probably the easiest to imagine as a product, basically a “gene in a bottle” that a physician could take off the shelf and administer to the patient. The bottle would contain the new genes in a vector system; the vector is the means of getting the genes into the cells of the body. Viral vectors are one type being studied by a number of researchers. When a virus infects a cell it inserts its genes into the cell which causes the cell to produce more viruses. By genetic engineering the viral genes can be replaced with, for instance, a factor IX gene. When this viral vector is injected into the body and the viruses infect cells, instead of producing more viruses the cell would produce factor IX. Many studies in animals have shown that this actually works: the infected or “transformed” cells begin to produce factor IX. The problem, however, is that the factor IX production often only lasts a few weeks. It appears that the body’s immune system see these transformed cells as harmful and eliminates them as though they were infected with normal viruses. Researchers continue to look for better vectors to overcome this problem.

The ex vivo method may be performed using either cells obtained from the patient or generic human cells grown in the laboratory. Using the patient’s own cells usually eliminates problems of rejection of the transplanted cells by the patient’s own cells usually eliminates problems of rejection of the transplanted cells by the patient’s immune system. However, the use of generic, factor IX-producing cells might be more convenient since they could be pre-packaged , ready to be implanted in the patient. The factor IX gene can be introduced into the cells by a number of techniques. These include viral vectors as described above as well as additional methods which work in the laboratory but could not be used in vivo, in the body. Researchers are studying a number of ways of implanting the transformed cells. Transformed muscle cells, for instance, might be surgically implanted back into a patient’s muscle tissue. Other types of cells can be injected subcutaneously, that is, just under the skin. To minimize the chances of the transformed cells being rejected by the patient’s body some studies have look at surrounding the cells with a porous membrane. The membrane is like a tiny plastic bag which can be implanted subcutaneously. It has pores large enough to let factor IX diffuse out but small enough to keep the larger antibody molecules from diffusing in to attack the cells.

An ex vivo method has been tested in China in two hemophiliac brothers aged 9 and 13. The approach was quite successful with the younger brother. His factor IX level increased to about 6% of normal with a corresponding decrease in bleeding problems. This has been maintained for a least six months at the time the study was published. However, for reasons that are not clear, no improvement was seen for the older brother. These results are encouraging, but further work is obviously needed.

Thus interest in gene therapy is increasing with many different approaches being studied. Although many problems still exist, a number of techniques look promising. With this potential for success companies are investing large amounts of money in the race to commercialize this technology, and the goal of a “cure” for hemophilia by the end of the century many actually be within reach.

WANTED - Adults with severe hemophilia B to participate in a phone interview survey. Participants will be asked their opinion on a variety of aspects of hemophilia B treatment and will receive $30.00.

Each interview may last about 30-45 minutes. The individuals name will be kept confidential by the company and any comments made will be pooled with those from other interviews. Interested individuals may call 1(800) 819-8239 to participate in the study.