Gene Therapy
Improves Quality of Life
for Patients
With Hemophilia

By Leslie Mertz

People with hemophilia have had a particularly rough time for the past three decades. Beyond the often-dangerous bleeding episodes, internal hemorrhages, excessive bruising and potential for debilitating joint disease, patients with hemophilia got bad, and then worse news about the only real treatment they had to control the bleeding. In the 1970s, they learned that their treatment, which provided them with a clotting factor that was produced from plasma obtained from 20,000-30,000 different persons, was almost universally transmitting hepatitis. By the next decade, the most devastating blow came: The clotting factor had been infected with HIV since the late 1970s, exposing the majority of U.S. hemophilia patients to the AIDS virus. 

Dr. Luscher recently infused the first hemophilic patient in the midwest with a retroviral vector containing the gene for normal factor VIII.

Fortunately, the future is getting brighter, according to Jeanne Lusher, MD, WSU distinguished professor of pediatrics and director of the Hemophilia, Hemostasis and Thrombosis Center at the Children’s Hospital of Michigan. She is part of a promising clinical trial that is giving patients renewed hope for success in the battle against this hereditary disorder.

One of the first patients to sign up for the trial was 53-year-old James Westbrook. “I have a grandson with it (hemophilia), and I would like to see him avoid the kind of problems that I've had. That was my primary reason for doing it.” In addition, he indicated that although many of the past problems with the currently used hemophilia treatment have been resolved, it still carries a slight possibility of transmitting some disease other than AIDS. The best solution would eliminate the reliance on that treatment altogether, he commented. “Thinking of that is why I thought it was a good idea to get involved and help a little if I can.”

The history
In people without hemophilia, bleeding stops when a series of clotting proteins, or factors, combine to make blood coagulate. Hemophilia patients – the vast majority of whom are men – are missing one factor, because they lack the gene to make it, Dr. Lusher said. In the more-common type “A” hemophilia, patients are missing the clotting factor known as factor VIII. Hemophilia B patients lack factor IX.

For the currently used treatment, hemophilia patients receive injections of the factor that they lack. The factor doesn’t last long, however, so the patient must receive additional treatments at frequent intervals – daily to every few days. In some cases, patients may make small amounts of the factor, but require the treatments to boost their levels. Past problems with the treatment arose because pharmaceutical companies concentrated the clotting factor preparations from huge volumes of starting plasma, described Dr. Lusher, who is also chair of the National Hemophilia Foundation’s Medical and Scientific Advisory Council. “Most of the companies put a minimum of 20,000 different people's plasma in the starting plasma. All it took was one of the people to have the hepatitis virus or HIV to contaminate the whole batch. By the end of the 1970s, it became apparent that almost everyone who was getting these concentrates was getting hepatitis, and by the early '80s, the AIDS epidemic almost decimated the hemophiliac population. It was a terrible time.”

Pharmaceutical companies now take additional steps to protect plasma-derived factors from being infectious, but the factors still carry a small risk of contamination by some blood-borne pathogen, she said. A newer and more expensive treatment, known as recombinant clotting factor, is being developed. Human factor VIII or IX genes are transferred into well characterized hamster cells. The hamster cells then produce human factor VIII or factor IX, and release it. These treatments are safer, but demand often exceeds supply, she observed. “We're having to scramble right now to get enough for our patients.”

The trial  
If successful, the trial ongoing in Dr. Lusher’s center and four others around the country would not only turn around the fight against hemophilia, but could give gene therapy a firm nudge as a viable medical option for many other disorders.

The trial, which focuses on hemophilia A, involves a potentially one-time treatment that would prompt the patients’ own cells to make the blood-clotting factor they lack. “With gene therapy, it's a matter of getting the normal gene for human factor VIII into the patient’s own body cells in such a way that those cells will be able to produce a normal factor VIII,” she said.

To do that, researchers had to insert the desired gene into a virus. As a safety precaution, they altered the virus so it was unable to cause infection or spread to other, unintended cells. Then, they did a little genetic editing. “The gene for factor VIII is one of the largest genes known, so we are using a truncated factor VIII gene which has had the whole middle section (called the B domain), which appears to be dispensable, taken out. This makes the gene much smaller, so it fits neatly into human cells.”

In addition, researchers opted to use a retrovirus as the vector to carry the factor VIII gene. A retrovirus is an RNA virus that invades a cell, makes DNA copies of its genes, then splices the copies into the host cell’s chromosome.

Patients receive this gene therapy intravenously, Dr. Lusher said. Once injected, the virus travels to the patient’s liver cells, where it transfers its genetic material – in this case, the gene for factor VIII. Ideally, each cell responds by incorporating the factor VIII gene into its own genetic material, which essentially is the instruction booklet the cell follows to make its battery of proteins. Unable to differentiate from the original genetic material and the new factor VIII gene, the cell follows the directions in the new gene and starts making normal factor VIII.

When the gene-carrying virus became available for patient testing last year, Dr. Lusher joined the trial and infused the first patient in the Midwest with the retroviral vector on June 5, 2000.

Dr. Lusher's lab is servicing as the central laboratory for this national, multicenter gene therapy trial.

The findings  
Although only about halfway through the year-long trial, Dr. Lusher said they are already seeing positive results. “Some of our earlier patients seem to be producing low levels of factor VIII, and some aren't taking (conventional treatments of) factor VIII nearly to the extent they were before.” Both are good signs, but she cautioned that this phase I research trial is still too new to draw definitive conclusions.  “Some of this may be a placebo effect, because these subjects really want this to work.”

Westbrook is one such patient. Although his factor VIII levels haven’t improved appreciably, he reported in late October that he hasn’t had to return to the conventional treatment for more than two months. “I am bleeding less, I’m getting fewer bruises and I haven’t had to treat since August, so something good is happening.”

Dr. Lusher reported, “It is promising, but it's in its infancy. It's not ready for everyone with hemophilia to line up and get gene therapy. It's far from that, but I think it's a very exciting development, and hopefully we will have success.”

She pointed out that two other phase-one trials for hemophilia A and B are also under way, and the trial for hemophilia B shows that patients are beginning to make low levels of factor IX. “Everyone’s using a slightly different method, but we’re all trying gene therapy as a potential treatment for hemophilia.”

Dr. Lusher, who is also a member of the data and toxicity monitoring board for the ongoing phase I trial for hemophilia B, anticipates that two additional gene therapy trials for hemophilia, using somewhat different approaches, will begin in early 2001.

The hope
As it turns out, gene therapy and hemophilia are a good match, Dr. Lusher said. “Hemophilia is thought to be one of the diseases most amenable for gene therapy because you don't have to hit a certain target level of factor VIII or factor IX. With other diseases, like diabetes, you have to be careful that the gene for insulin doesn’t make too much or too little. Either could be detrimental.” Target levels for factor VIII and IX, on the other hand, are broad. Even two or three percent would make a tremendous difference for someone with severe hemophilia, resulting in a drastic reduction in bleeding episodes. “You can have different levels, and the more the better.”  

Now that initial results indicate that gene therapy is generating at least some clotting factor in trial patients, the work is drawing the attention of the scientific community. “There's more and more interest in hemophilia, because this seems to be working, plus there seems to be no toxicity to the patients,” Dr. Lusher remarked.

She stressed that each of the trials is proceeding under tight safety precautions and the watchful eye of the Federal Drug Administration’s gene therapy branch. Dr. Lusher’s trial, for example, is employing standard dose-escalation protocol: The first patients in the trial received a lower dose of the viral vector to help ensure its safety, and later patients are taking higher and higher doses. “We followed those first patients for 12 weeks to make sure that everything was going well with them before we gave the next group of individuals the next dose.” In addition, she said participating patients also go through a series of physical exams, as well as frequent blood and semen tests to ensure that the retroviral vector is doing its intended job and nothing else.

Gene therapy may change the future for new generations of patients like three-year-old Erik Malone who suffers from severe hemophilia.

She noted that the Hemophilia, Hemostasis and Thrombosis Center is the central lab for the entire study, so it is responsible for testing the factor levels for all patients in the five-center trial. “One of the many nice things about being here at Wayne State and Children’s Hospital is that we are involved in a lot of new research. That keeps our research teams enthused, plus it gives our patients access to new treatments before they’re available in most parts of the country.”

So far, Dr. Lusher is quite encouraged by the interim results of the gene therapy trials for hemophilia. “As long people continue to do well with no deleterious effects, I’m sure it will become a new treatment for hemophilia, but it’s really hard to say how soon that could happen. Hopefully, we will have a much better idea in the next year or so.”

The coming months will also present a better picture of the impact the work may have on gene therapy as a whole. “If this works for hemophilia, it could be a great benefit for gene therapy in general, because a lot of the same issues apply, like the immune response to the vector, toxicities, getting the vector in enough of the right cells and so forth. There are a lot of things the technology is useful for disease-wise. It's quite exciting.”