Fall 2001 - Factor Nine News

Earlier this year I was asked to speak at the annual meeting of the Federacao Brasileira de Hemofilia (Brazilian Hemophilia Federation) in Sao Paulo, Brazil on behalf of Genetics Institute. Dr. Keith Hoots (from Houston) and myself went to give a United States perspective from that of a physician treating, and a patient with hemophilia. Dr. Hoots spoke of the advantages of recombinant technology and I spoke about what it has been like to be an American with hemophilia.

As I researched the audience I was to speak to, patients, medical personnel and governmental officials, I found many differences in our cultures and healthcare. Sao Paulo city has approximately 36 million people ranging from great wealth to great poverty. I was amazed to see very expensive high-rise condos with poverty cities right next to them. These poverty cities were nothing more than whatever could be found to create some type of shelter. They cooked their food on open firebarrels and had no plumbing. The poverty theseendure humbles me for what I have been blessedwith here in the United States. Sao Paulo seems to be more crowded by cars than people; each car seemed to have just one passenger in it and the paint lane markers were really there for decoration. If you were to drive there you might feel inclined to have an episode of road rage at they way they drive but it is just the way they have learned to share the road. Our hotel was located near the center of the city and when I looked out the top floor windows, it seemed to stretch as far as the eye could see. As I wander the city on my own, speaking the very basic of Portuguese, I found the natives to be very friendly and helpful.

Brazil has many remote areas. Some persons with hemophilia have to travel hours to see a physician, only to be told that they are not having a bleed and sent home. If they are having a bleed, they hope they have not exceeded their yearly allotment of 30,000 units of factor. I find this quite disturbing. How can someone tell a hemophiliac they are not having a bleed when they can feel it? And how can a socialized medical system justify limiting an individual’s access to coagulation products?

At the meeting, I explained my role as a consumer advocate and how homecare works in the USA.I also addressed a variety of issues. To the patients, I shared some of the history of our community; and how having immediate access to clotting factor has made such an impact on my quality of life and how our community is now keeping a vigilant eye on product safety. I encouraged them to seek self-empowerment and advocacy and told them to try to effect positive change through positive pro-active measures. I expressed my feelings of brotherhood and sisterhood regardless of where you live or come from.

As I continued, I explained how our community had banded together to achieve success in obtaining home treatment and the passage of the Ricky Ray Law. I also encouraged them to become advocates for their own healthcare, as well as for those who are unable to advocate for themselves. Also discussed was the importance of working with those who affect our care, i.e.,pharmaceutical companies, medical staff, government and insurers.

To the medical staff, I spoke about partnering with the patient in their care and having immediate access to factor. I urged them to remember that we know our own bodies, and that early treatment reduces physical and emotional damage. One man asked me an important question, “How can I justify the cost?” As the interpreters were repeating his question for me, a small boy with severely damaged knees was walking up the main aisle back to his seat. I asked the young man to stop where he was for all to see. Then I respondedto the question by saying, “What is this child’s life worth?” The gentleman turned his head and looked to the ground.

And to the governmental officials, I spoke about the cost of not providing necessary care. In other words, what is the cost of a human life and the quality thereof. I challenged them that th long term effects of not having adequate clotting products are more costly in terms of future medical expense and lost payroll tax revenue.

Stem cell research has been in the news recently because of the controversy over whether embryonic stem cells should be used to develop new medical treatments. However, there are a number of other types of stem cells that do not carry with them the political, ethical and religious issues that surround embryonic stem cells. Recent research has shown that some of these other types of stem cells may be useful when used in combination with gene therapy methods to develop better treatments for a number of diseases, including hemophilia.

Gene Therapy is a very active field of research that in recent years has been considered the most likely technique for eventually developing a “cure” for hemophilia, as well as for many other diseases. Hemophilia B arises when the gene that tells the liver how to produce Factor IX proteins is defective. This causes the body to either make a Factor IX that has the wrong structure or, in some cases, to produce no Factor IX at all. The idea behind gene therapy for hemophilia B is to introduce a good Factor IX gene into selected cells in the body and cause it to produce enough Factor IX to restore the clotting ability of the blood.

This has turned out to be much harder than researchers had originally hoped. Over the years, this newsletter has printed several optimistic reports on gene therapy experiments. The outlook is still optimistic, but much work remains to be done. The three main challenges in gene therapy are: 1) deciding what cells in the body would be the best ones to target to produce the new Factor IX, 2) obtaining the correct gene to insert in those target cells and 3) finding a way to get enough copies of the gene into enough of those cells. The target cells can theoretically be any cells that have access to the bloodstream.

Among other types of cells, researchers have targeted liver cells because Factor IX is normally made in the liver. They have also targeted skin and muscle cells because they are more easily accessible than internal organs such as the liver.

The correct gene includes not only the DNA that tells the cell how to make Factor IX, but also regulatory sequences. The regulatory sequences are sections of the gene that determine when, where and how much Factor IX will be produced.For instance, the regulatory sequence in a normal Factor IX gene causes it to be produced in the liver at a rate that will maintain the correct Factor IX level in the bloodstream. Finding the right gene for gene therapy means finding a regulatory sequence that will work in the target cells to produce the right amount of Factor IX.

Many different methods have been tried for getting the new gene into the target cells. One popular method is to create viruses in which some of the viral genes have been replaced by, for instance, Factor IX genes. These viruses are then introduced into the body to “infect” the target cells with the Factor IX genes instead of with the virus genes. Another method is to simply inject DNA pieces that include the new gene into muscle tissue where some of it will be taken up by muscle cells.Target cells can also be removed from the body to have the new gene inserted in the lab where cells can be handled more easily. The altered cells are then re-introduced back into the body.

Most of the Factor IX gene therapy methods that have been tried so far have only been partiallysuccessful. A common problem is to modify enough cells so that a large enough amount ofFactor IX will be produced.

The other major problem is that Factor IX production often decreases and eventually stops after a period of time. Stem cell therapy can potentially be used to solve some of these problems.

Stem cells are cells in the body that have not differentiated. That means that they have not turned into any specific kind of cell such as liver cells or brain cells. Stem cells have all of the same genes as all other cells in the body, but the regulatory sequences of the genes that would tell the cell to be a liver cell or a brain cell have not been activated. They are like a kid who does not yet know what he is going to be when he grows up. It has recently been discovered that many organs in the body contain stem cells that the organ can activate to replace other worn-out or damaged cells.

One of the major types of stem cells is the hematopoietic (Greek for “blood making”) stem cell. These stem cells can turn into any of the various types of blood cells: red cells, white cells and platelets. Hematopoietic stem cells reside mainly in the bone marrow, in the center of the large bones of the body. These stem cells are continually being activated to produce new blood cells as replacements for old or damaged blood cells. Hematopoietic stem cells, like most other types of stem cells, can also replicate to produce more stem cells. That keeps the bone marrow from running out of stem cells as they are being used up in producing more blood cells. Bone marrow transplants, which are basically hematopoietic stem cell transplants, have been used for years to treat diseases such as leukemia.

One advantage of hematopoietic stem cells is that they are easier to collect than most. That is not to say that harvesting bone marrow is simple; it is ahospital procedure. It is just that harvesting most other types of stem cells is even more difficult. Researchers have also recently discovered that one type of stem cell can be made to change into another type of stem cell. For instance, hematopoietic stem cells could be reprogrammed to be liver stem cells, thus providing an easier method to obtain liver stem cells.

The basic idea in combining gene therapy and stem cell therapy is that a new gene could be inserted into a group of stem cells. Those stem cells would then be inserted into the body where they would produce more and more cells that contain the new gene. For instance a Factor IX gene could be inserted into hematopoietic stem cells in the lab after which the cells would be reprogrammed to be liver stem cells. Those modified cells would then be injected into the liverwhere they would act just like other liver stem cells to produce new liver cells. Those new liver cells would then have the capability of producing normal Factor IX.

Gene and stem cell therapies have the potentialto revolutionize the treatment of many diseases, including hemophilia, but there are still a huge number of issues to resolve. Gene therapy is a relatively new field and stem cell therapy even newer. The basic ideas described above are fairly well understood, but many of the important details are still unknown. However, these fields are at the forefront of medical research with new discoveries everyday. There is every reason to believe that the dream of a cure will be realized in the next several years.

National Hemophilia Foundation
53rd Annual Meeting
November 15-17, 2001
Nashville, Tennessee
Contact NHF:800 424-2634

Also at the NHF Conference we will once again hold a Factor IX Family Meeting.For more information visit us at our booth.

We hope to see you there!