Spring 1998 - Factor Nine News

Everything we have described about chimeraplasty so far was based on work done in test tubes. However, this March researchers at the University of Minnesota Medical School published the results of a study in which they were able to modify the Factor IX gene in rats using this technique. Since rats do not normally have hemophilia, the reverse experiment was done; the rat’s Factor IX genes were modified to give them hemophilia. This was the first demonstration that chimeraplasty could be used to modify genes in living animals.

These experiments actually involved more than just chimeraplasty. Another major challenge is getting the chimeric drug into the cells of the liver where Factor IX is made. The Minnesota group specializes in liver research and was able to modify the drug so that it would bind to a certain receptor molecule that is on the surface of liver cells. Various types of receptors are present on most cells. This particular receptor only occurs on liver cells and is used to catch certain proteins from the bloodstream and bring them into the cell. By making the chimeric drug look like the type of protein that is recognized by this receptor, it was possible to simply inject the drug into the bloodstream and have it end up in the liver cells.

This is a spectacular result, but it is just the beginning of a long process. What is very exciting to us is that this research is carried out on factor IX. Hemophilia B is very much in the lead in gene therapy research. We will be one of the first to benefit from the development of gene therapy, and all signs are that this will be a “cure”. We will continue to work as hard as we can to push this area forward and perhaps in ten years it will be available to everyone.

Recombinant Update

In other news, MASAC, the Medical and Scientific Affairs Committee of the National Hemophilia Foundation, was provided with an update on recombinant Factor IX, BeneFIX^TM, for their February meeting. BeneFIX was licensed in the U.S. last year and has been used successfully in treating patients. However, one of the issues surrounding the product is that it exhibits a lower recovery than plasma-derived Factor IX products. Recovery refers to the amount of Factor IX that is seen in the bloodstream after an injection. With plasma derived Factor IX only about half of the amount injected can be detected in the bloodstream; most of the rest binds to the cells that line the blood vessels attached to another type of receptor. For unknown reasons, when BeneFIX is injected, about 20% less shows up in the bloodstream, that means about 40% of the amount injected. Because of this the instructions for using BeneFIX call for a 20% increase in the amount infused, compared to plasma-derived products. Genetics Institute, the manufacturer, has been doing extensive studies, both in the laboratory and with patients, to determine the cause of the lower recovery.

Results show that the lower recovery is apparently due to small differences in post-translational modifications of the recombinant Factor IX. Translation is the process a cell uses to make a protein from the recipe given in the gene. Post-translational modifications are changes that the cell makes to a protein after the basic molecule has been formed. These modifications are often one of the main stumbling blocks in trying to produce proteins by genetic engineering. Often the cells used to produce a recombinant protein in large amounts do not modify the protein exactly the same way that the body’s cells do. This often does not affect the function of the protein, but sometimes it can. The recombinant Factor IX in BeneFIX is just as effective and stays in the bloodstream just as long as plasma-derived Factor IX, but because of slight differences in the post-translational modifications, the recovery is lower. However, the usefulness of any drug is not determined by whether it is identical to another, but rather whether it does its job in a predictable manner. Genetics Institute has shown that their product has been consistent by a number of biochemical tests during their four years of production in which over 300 million units in over 150 batches have been manufactured. Thus, at this point there is no reason to doubt that BeneFIX is a effective product when used as directed. However, further studies are being done to analyze the variations in levels and half-life that might be seen in different individuals. The questions being asked concerns the range of recovery that has been noted in certain cases. We will report on these studies as soon as they are completed.

Blood Safety

Finally, some news from the annual conference on blood safety held in February. The first day was devoted to discussions about transmissible spongiform encephalopathies (TSE’s), the unusual diseases like Creutzfeld-Jakob disease in humans and “mad cow” disease in cattle. Learning from the experience with AIDS, the blood industry is preparing to deal with such diseases before it is even known whether they can be transmitted by blood products. So far, the risk of transmitting TSE’s by blood or plasma products is purely theoretical, no cases of transmission have ever been seen.

Of more immediate impact, several of the plasma fractionators, including Alpha and Centeon, manufacturers of the two Coagulation Factor IX products currently available, described their plans for starting PCR testing of their plasma pools to detect viral contamination. PCR stands for Polymerase Chain Reaction, a relatively new and very sensitive technique for detecting specific DNA sequences. PCR techniques have been developed that will allow detection of individual plasma units that contain the DNA of specific viruses such as hepatitis C and HIV, the AIDS virus. PCR will mainly identify units that were donated during the “window period”, the time between when a donor comes down with a viral disease and when his body starts making antibodies that can be detected by the current testing methods. While PCR testing will only detect a tiny number of units that were not already screened out by the current tests, the plasma industry realizes that product safety is the key to the continued acceptance of plasma-derived products.