Winter 1997 - Factor Nine News

News from the American Society of Hematology (ASH) annual meeting held December 5 - 9, 1997, in San Diego, California. Hematologists who specialize in treating blood-associated diseases including hemophilia, meet once a year to learn about the latest research and treatment methods. More than 10,000 attend with about 3,000 from outside the United States.

The Coalition for Hemophilia B holds a breakfast symposium every year at the ASH meeting, and this year it featured talks by Dr. William N. Drohan of the American Red Cross and Dr. Mark Kay of the University of Washington. Other scientists and doctors are the listeners. Dr. Drohan discussed recent work on the risk of prions to be transmitted by blood and blood products. Prions are infectious particles that cause rare, fatal brain diseases such as Creutzfeld-Jakob disease (CJD) in humans and “mad cow disease” in cattle. No one knows whether prions can be transmitted by blood, and this is a major focus of current research. Dr. Drohan described the pace-setting research in this critical area. It involves several animal studies that the Red Cross is doing in collaboration with the National Institutes of Health and the VA Medical Center in Baltimore. This work is partially sponsored by the Coalition. By infecting mice or hamsters and then transfusing their blood into other mice or hamsters, the team hopes to be able to determine whether such blood is infectious. They will also separate the blood into its various components such as red cells, platelets, and plasma, and then fractionate the plasma to see which components if any, might carry the infectivity. These experiments take over a year to complete, so we will probably have to wait until next year’s meeting to find out the results. Call us if you want to chat about these results before they are final.

Meanwhile, the Red Cross has also been doing studies of patients who have received blood transfusions from donors who later died of CJD, and so far there is no evidence of CJD transmission. Thus it seems likely that blood and plasma products either do not transmit CJD , or do so extremely rarely. Just in case, makers of plasma products are also looking at ways to inactivate or remove prions from concentrates such as factor IX. The Red Cross has probably found one and the FDA is very interested.

Dr. Kay discussed factor IX gene therapy, the potential “cure” for hemophilia B. As we discussed here recently, the use of viruses to deliver good factor Ix genes to the body faces the dual challenges of producing enough factor IX and having the production persist for the patient’s lifetime. The use of retroviruses gives persistent production, but usually too little factor IX. Other viruses like Adeno associated viruses (AAV) give factor IX levels, but the production gradually dies away. Dr. Kay’s groups has potentially found a way to solve the problem with Adeno associated viruses (AAV). Factor IX gene therapy is often directed at the liver which is where factor IX is normally made. However, retroviruses only infect dividing cells and the liver contains few dividing cells. This is probably the reason that not enough factor IX production is obtained, because too few cells receive the new gene.

In animal studies, Dr. Kay has discovered that giving a growth factor to an animal prior to the Adeno associated virus (AAV) produces a much higher level of factor IX production. Growth factors are small proteins that can affect cells in many ways, in this case causing them to divide. The liver was seen to grow appreciably over the several days that the growth factor was being administered and then return to its former size after the growth factor was discontinued. Using these findings Dr. Kay has been able to generate lasting high levels of factor IX production in animals. If further studies continue to support this, it could become a significant step toward the successful use of gene therapy in patients.

Saturday and Sunday, ASH holds education sessions that present the state-of-the-art in scientific knowledge and treatment methods. There were two sessions on hemophilia which each included several excellent presentations by renowned researchers and clinicians. One presentation summarized the viral safety of current clotting factor concentrates. It concluded that plasma-derived products have become extremely safe, though not perfect; there are still rare reports of infection, luckily, none in factor IX. However, the higher cost of the presumably safer recombinant products is a problem for many patients, so work continues on making the plasma-derived products as safe as possible. Another presentation discussed issues in prophylactic therapy in which daily doses of clotting factor are given to prevent the progressive joint disease from which most hemophiliacs suffer. This is still an experimental method with many open questions such as to the best age to initiate treatment, the optimum dosage and frequency of administration, whether the type of product used affects the result, and the most convenient route of injection. Prophylactic treatment also improves many psychosocial issues for both the patient and his family but creates significant financial issues. In spite of these issues, it can change the lives of hemophiliacs and prophylactic treatment holds great promise for improving the health and well-being of hemophiliacs.

The next talk discussed treatment of patients who develop inhibitors. Inhibitors are antibodies that the body develops because it sees the clotting factor as a foreign material. Because inhibitors inactivate the clotting factor they greatly complicate treatment. Although 21-33% of hemophilia A patients develop inhibitors, only 1 - 6% of hemophilia B patients do so. However, anaphylaxsis is a very difficult hemophilia B problem that has not been well addressed and a lot of work needs to be done.

The last two talks reviewed the various clotting factor concentrates available and the current status of gene therapy, which we discussed above. Other individual presentations throughout the meeting showed the results of recent studies on various aspects of factor IX and hemophilia B. As usual, the ASH meeting was an excellent update on the current state of knowledge and treatment methods. If you are interested further we can send the papers to you and would be happy to talk.

One last note of interest learned at the meeting concerned Dolly, the cloned sheep that was in the news several months ago. It turns out that Polly, the second cloned sheep, is a transgenic animal that produces factor IX in her milk. As we have discussed here before, production of recombinant proteins in transgenic animals looks like the best way to increase the supply and reduce the cost of these proteins. One of the problems with transgenic animals is that just like humans, each animal is a little different. Some produce higher or lower amounts of the protein, and some may even produce slightly different forms of the protein. Dolly was not made just to do something interesting, cloning seems to be an easy way to produce a herd of identical animals that all produce the same protein at the same level. It is wonderful that the very first animal in the world to do this has factor IX in her milk. We are on the front line.

For more information please call Kim Phelan at (212) 554-6823.