Fall 1997 - Factor Nine News

Gene therapy is seen as a potential “Cure” for hemophilia B. Through gene therapy techniques, good working copies of the gene for Factor IX would be introduced into the body to produce Factor IX continuously throughout the rest of the patient’s lifetime. This is easier said than done, but researchers are steadily edging toward success. One advantage for us is that much of the gene therapy research being done is focussing on Factor IX. Even though hemophilia B affects a relatively small number of people, the disease and the Factor IX protein have a number of advantages that make it a good model system. Thus many scientists who had no previous involvement with hemophilia research are using Factor IX as a test case for developing general methods of gene therapy that could be used to treat many different genetic diseases.

There are many potential ways of doing gene therapy, but they basically boil down to either introducing new genes directly into the body in ways that get them into the proper cells, or else transplanting cells which already contain active Factor IX genes into the body. The first method, directly inserting the genes into the body’s cells, has mainly been attempted using viruses. A virus is really a tiny mechanism for injecting genes into cells. Once inside, the virus genes take over the cell and use it to make more viruses. What researchers have done is to replace some of the virus genes with a Factor IX gene. Then when a person is infected with these modified viruses, instead of getting sick he starts producing Factor IX.

Many different types of viruses have been tried, but so far they all have limitations. Using one type called a retrovirus, scientists have been able to get hemophiliac dogs to produce Factor IX. However, the amount of Factor IX produced in even the most successful experiments has been much too low to be effective. Apparently the infection rate with retroviruses is too low to be able to easily “infect” enough cells. To get around this, experiments have been done with another type of viruses called adenoviruses. With adenoviruses they have been able to produce tremendous quantities of Factor IX, as much as 300% of normal, but the Factor IX production dies out in a few weeks. The animal’s immune system apparently recognizes the cells as being infected and attacks them. This has been the story of viral gene therapy so far: you either get too little factor IX but have it last for the animals lifetime, or you can get an effective amount but it dies out in a few weeks. Because of the larger amounts of Factor IX produced using adenoviruses, much current research is focussing on modifying them to eliminate the immune reaction and allow the Factor IX production to persist.

Another interesting approach was recently announced by researchers at Brown University. They have developed micropsheres, tiny round shells less than 1/10,000 of an inch in diameter, that can be filled with proteins or genes. Although they have not worked with Factor IX yet, they have shown that when gene-filled microspheres are fed to rats, the genes are apparently taken up in cells and the protein produced from the genes appears in the rat’s bloodstream. Incidentally this work has also shown that these microspheres can deliver proteins to the bloodstream, a finding that could be used to develop an oral version of Factor IX.

The other primary way that scientists have looked at doing gene therapy is by injecting whole cells containing active Factor IX genes into the body. These can be either cells that were originally removed from the patient’s body or other human cells from laboratory cell lines. The advantage to using a laboratory cell line is that a consistent well-characterized off-the-shelf product could be developed for the physician to use. However, this is offset by the fact that the patient’s body will see these cells as “foreign” and try to reject them. This foreign body reaction can be avoided only by suppressing the patient’s immune system with drugs or by encapsulating the cells in a membrane which would isolate them from the immune system but still allow Factor IX to diffuse out to the bloodstream.

Using the patient’s own cells is a more complex process at the time of the treatment, but may be less problematic in the long term. This would involve first removing some cells from the patient’s body, “infecting” them with the Factor IX gene, and then using those cells to grow a large number of cells in the laboratory. At that point the modified cells would be re-implanted into the patient’s body in the same way that an off-the-shelf cell line would be. Scientists are exploring the use of several different types of cells including skin cells, liver cells, bone marrow cells, muscle cells, and the cells that line the blood vessels.

The challenges with the cell method are similar to those for the other methods, getting enough cells to produce an adequate amount of Factor IX, and getting the production to continue. However, scientists in China have actually implanted modified skin cells into two patients with moderately severe hemophilia B and have shown a small but lasting increase in Factor IX levels. Skin cells from the two patients were modified to include good Factor IX genes and the cells were re-implanted under the skin. Their Factor IX levels increased from about 2% of normal to about 4% and the increase has persisted for over a year.

The development of gene therapy for hemophilia B still has a number of challenges to overcome, but a great deal of research is going on and scientists are rapidly gaining much insight into the processes involved. There is a very good chance that within a few years the dream of a cure will become a reality.

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