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Factoring in: Potential treatment for hemophilia

Of all genetic diseases, this family of bleeding disorders is among the lead contenders for successful gene replacement therapy. But the promise is accompanied by caution.

By Susan J. Landers, amednews staff. May 6, 2002.

Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

"About 70 or 80 years ago a woman by the name of Smith ... transmitted the following idiosyncrasy to her descendants," wrote John Conrad Otto, MD, in 1803. "If the least scratch is made on the skin of some of them, as mortal a hemorrhage will eventually ensue as if the largest wound is inflected."

Most would readily recognize this description of hemophilia.

A long time coming
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Dr. Otto also had concluded that the disease was linked to the X chromosome. "It is a surprising circumstance that the males only are subject to this strange affection," he noted. And, he knew that women were carriers. "Although the females are exempt, they are still capable of transmitting it to their male children," he wrote.

But Dr. Otto didn't know that the passage of time would bring great potential for treatment and even a possible cure.

In the 200 years since his observations were first published, great gains have been made in the treatment of people with various types of hemophilia, thanks to advances in transfusion medicine, blood safety and a better understanding of the disease. Now a push for a cure for hemophilia has been mounted and gene therapy appears to be the way to go.

Five phase I clinical gene therapy trials are underway, and other trials are ongoing using animal models.

Hemophilia A affects one in 5,000 men; hemophilia B affects about one in 20,000 men.

The National Hemophilia Foundation has set a cure for the disease as one of its goals and mounted a fundraising effort. "We think it can happen, and rather than wait to see it happen in some other disease, we'd like to see investigators try different approaches, different vectors and different gene delivery systems in hemophilia," said Glenn Pierce, MD, PhD, the foundation's president.

The foundation is now funding gene therapy research as are commercial companies and the federal government.

"I think [gene therapy] is a real hot deal. ... It probably won't be available to the public this year or next year, but it is really moving," said Jeanne Lusher, MD, director of the Hemophilia, Hemostasis and Thrombosis Program at Children's Hospital of Michigan in Detroit.

Of all the genetic diseases, the so-called bleeding disorders have characteristics that make them likely candidates for successful gene replacement therapy. And much of the optimism about a cure via gene therapy is attributed to the nature of the disorder, said Richard "Jude" Samulski, PhD, director of the Gene Therapy Center at the University of North Carolina at Chapel Hill.

Hemophilia is a group of hereditary bleeding disorders caused by the lack of a single gene product in the blood. This missing product can be triggered by a wide variety of genetic flaws or mutations and presents in varying degrees.

In hemophilia A, which affects about one in 5,000 men, factor VIII is lacking, and for hemophilia B, which affects about one in 20,000 men, the lack of factor IX is responsible for the disorder. Another type, von Willebrand's disease, which affects men and women, is, in most cases, relatively mild.

60% to 70% of severe hemophiliacs became infected with HIV from unsafe blood products.

But in general, hemophilia "doesn't require fully correcting the deficiency in order to make a clinical dent in the patient's performance," said David A. Roth, MD, assistant professor of medicine at Harvard Medical School, who is running a clinical study on hemophilia and gene therapy at Beth Israel Deaconess Medical Center in Boston.

Because hemophilias occur in mild, moderate and severe forms that are separated by only small amounts of a plasma coagulation factor, researchers can achieve a high level of success if they can increase the clotting factor in an individual's blood by even a few percentage points.

In practical terms it means the difference between receiving infusions of clotting factor as many as two or three times a week to being able to make sufficient amounts of the factor to avoid the hundreds of thousands of dollars that the infusions cost each year.

"Someone who has the severe disease may bleed every week, 30 to 50 times a year, whereas a person with mild hemophilia may only bleed following a tooth extraction or surgical procedure. That would be really something," said Dr. Roth of such a transformation.

Researchers in hemophilia also face a less daunting challenge than do, for example, researchers in muscular dystrophy or in cystic fibrosis.

"For hemophilia gene therapy, all one must do is get some of the factor protein delivered from the gene to the systemic circulation," said Dr. Pierce. "That's a tall order," he acknowledges. "But it's a much easier challenge than trying to get the dystrophin gene into every single muscle cell or trying to get the gene that causes cystic fibrosis into many of the stem cells that give rise to cells that are lining the lung. Those are bigger technical hurdles," he said.

Also, while the factors are normally made in the liver, they can be delivered elsewhere in the body for the purpose of gene therapy, Dr. Roth points out. "You don't have to introduce your cell therapy into a specific region of the body. As long as it can make its way to the blood stream, you're set," he said.

Dr. Roth is the principal investigator in a trial using patients' own skin to grow modified cells containing the gene for factor VIII. Other researchers are using viral vectors to carry the modified gene into the liver or muscle.

Safety first

Although a search for a cure is a high priority, researchers are proceeding with great caution. Those with hemophilia demand it.

"I think the hemophilia community is probably the best informed community out there," said Dr. Samulski. They were likely made more wary in the aftermath of the disastrous contamination of the concentrates of coagulation factors with hepatitis B and C in the 1970s and contamination with HIV in the 1980s.

It was estimated that 60% to 70% of people with severe hemophilia in the United States and Western Europe became infected with the AIDS virus before a virally inactive plasma concentrate was manufactured.

Now, "They come to our meetings and they stand up and tell us: 'We don't need a cure unless it is absolutely safe because we have a treatment,' " said Dr. Samulski.

Nor has anyone forgotten Jesse Gelsinger, who died in September 1999 after participating in a gene therapy experiment. "Suddenly gene therapy advocates could no longer claim that no one had been killed or harmed by gene therapy," noted Kevin Kelley, the parent of a son with hemophilia and the author of The Parent Exchange Newsletter that covers developments in the research and treatment of the disorder.

The Gelsinger case made it apparent that all the risks of gene therapy were not clearly understood, Kelley said.

So the burden is on the researchers, and they take the responsibility very seriously.

Dr. Samulski is focusing on the safety and efficiency of the adeno-associated virus as a vector for the modified gene. "We have spent time trying to make the vector become more robust," he said. Other researchers are taking the vector into clinical trials.

Dr. Roth also stresses the need for slow and careful product development. "If we focus on the issues that are most important at this time, which are safety issues, then we can have a strong foundation on which we can build huge progress," he said.

Clinical trials

A variety of approaches are being tried in ongoing clinical trials. "You name it and they've tried it," said Dr. Pierce.

Among the promising approaches is one being used at Children's Hospital of Philadelphia by Katherine High, MD, a professor of pediatrics. Dr. High and her colleagues are using the adeno-associated virus to deliver factor IX directly to the liver where the blood factors are made by the body.

Dr. High had first used the muscle to convey factor IX to patients with hemophilia B but found that the circulating levels of the factor were not high enough in most of the patients to really improve the symptoms of the disease, she explained.

Of the two paths open to the researchers -- either increase the therapeutic dose or try a different target cell -- they opted for the later.

Two subjects have been treated so far in the trial, which was designed for nine. It began last fall but progress was halted when traces of the vector were found in the spermatocytes of the first patient treated.

The traces have since cleared in that patient, and Dr. High is optimistic that the trial will soon move forward.

She is very encouraged by findings in a study using dogs with hemophilia B. In 1999, Dr. High's team of researchers announced that gene therapy achieved long-term improvement of naturally occurring hemophilia in dogs. That work produced levels of clotting factor in the dogs that would be therapeutic if achieved in humans.

"So I always think, if you can do it in a 20 kg dog, you can do it in a 70 kg man," she said. "But just because I believe it, it doesn't mean it's true," she cautioned. "But it's very, very encouraging."

Dr. Roth is also encouraged by his findings that were published in the June 7, 2001, issue of The New England Journal of Medicine.

Rather than use a viral vector, Dr. Roth used a nonviral form of gene therapy developed by Transkaryotic Therapies Inc. in Cambridge, Mass. Dr. Roth and colleagues removed skin cells from patients, genetically engineered them to produce factor VIII and reinserted the modified cells into a fat layer inside the abdomen.

The phase I trial revealed no serious side effects of the treatment and, as a bonus, plasma levels of factor VIII increased in four of the six patients.

However, the increases did not last, and it was unclear whether the cells died or stopped working.

Dr. Roth is continuing to analyze the data from that trial and is beginning work on a phase II study.

Genetic counseling

Hemophilia is a more complicated disorder than many others when it comes to counseling patients on their risk of having a child with the disorder.

The fact that women might not know their carrier status makes it more important for a physician or counselor to ask about the health of more distant relatives than would be the case for a disease like cystic fibrosis, for example.

If an individual has a first cousin with cystic fibrosis, the risk of that individual passing the disorder to her child is still relatively small, noted Vivian Weinblatt, past president of the National Society of Genetic Counselors, because a partner would also have to carry the cystic fibrosis gene.

"But if your mother's sister's son has hemophilia, the mother's sister could be a carrier, the mother could be a carrier and you could be a carrier," she said. A partner's status is unimportant.

In addition, the disorder may be more hidden than others because most hemophilia carriers are not symptomatic, said Weinblatt.

Another complexity arises from the disease's range in severity. For those with severe hemophilia who have less than 1% of the clotting factor, there is a DNA test that can be done -- but it doesn't work for everybody, said Weinblatt.

Some women with a family history of hemophilia may wish to have clotting studies done to see if their factor VIII or IX levels are depressed, she said. But the test is best done before pregnancy and clotting factors are elevated.

Testing could also be beneficial for the newborn, she said. An obstetrician should be aware of a baby's status before a circumcision, Weinblatt said. "And when the baby is born, that's a really good time to get him tested because you can take blood from the umbilical cord and you don't even need to stick him," she added.

ADDITIONAL INFORMATION:

A long time coming

References to hemophilia have been made since earliest history, but effective treatment leading to longer lives has occurred only in the last 40 years. Before then, those with a bleeding disorder often died in childhood. Now a person with hemophilia can expect to live a normal life span. These are some significant events that brought this turnaround:

1965 The development of a factor VIII-rich plasma preparation.
1982 Factor IX cloned.
1983 Factor VIII cloned.
1984 Virally inactivated plasma concentrates were manufactured, but most of the population was already infected with viruses that cause AIDS and hepatitis C.
1988 First patient treated with recombinant DNA produced factor VIII.
1999 First human gene therapy trials.
2001 First hint of activity in some patients who received factor IX or factor VIII gene therapies.

Hemophilia and a royal family tree

Queen Victoria and her husband, Prince Albert, had a great deal to do with raising the profile of hemophilia. Of the couple's nine children, one son, Leopold, had hemophilia. Two daughters, Alice and Beatrice, were carriers.

A look at their family tree shows how the disease proceeded to create havoc among European royalty for about a century.

Daughter Alice had seven children of whom one son had hemophilia and two daughters, Alix and Irene, were carriers. Daughter Alix became czarina of Russia when she married Nicholas in 1894. Their son, Alexis, had hemophilia.

Irene married her cousin Henry of Prussia, and two of their three sons were affected.

Queen Victoria's daughter Beatrice passed the hemophilia gene to the Spanish royal family, and of their four children, two sons had the disease.

The gene, which apparently arose as a spontaneous mutation, as no one in Victoria's family had the disease, seems to have run its course by 1945, when the last of Beatrice's sons died at 56.

The present British royal family is not affected because Victoria's son, Edward VII, the grandfather of Queen Elizabeth, did not have hemophilia.