Has Sickle Cell Met Its Match?

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The discovery of the abnormal gene that causes an inherited disorder is normally viewed as the first--and most important--step toward developing an effective treatment, perhaps even a cure, for the disorder.

Except for sickle cell disease.

Sickle cell was the first disease for which scientists knew the precise genetic defect at its root. More than 30 years ago, researchers discovered that the disabling disorder is caused by the presence of a wrong link in the long chain of chemical bases that form the gene for hemoglobin, the oxygen-carrying component of red blood cells.

Despite that knowledge, it has only been recently that physicians have been able to contemplate a cure--or even an effective treatment--for this disorder, which affects an estimated 80,000 African Americans.


Last month, a multi-center team of surgeons reported that bone marrow transplants--a “brute force” form of gene therapy--can cure the disease in the most severely affected children who are lucky enough to have a sibling who is a compatible donor.

And last week, researchers at Thomas Jefferson University in Philadelphia reported the discovery of a simple technique to trick the blood cells of sickle cell victims into repairing themselves, an approach that could have much wider applicability than bone marrow transplants. Clinical trials of this gene therapy could begin in as little as a year, according to Jefferson’s Dr. Eric Kmiec.

“We have a very strong need for new treatments,” said Dr. Kwaku Ohene-Frempong of Philadelphia Children’s Hospital, chief medical officer of the Sickle Cell Disease Assn. of America. And gene therapy, he added, “is the strongest hope for a universal cure.”

Sickle cell disease strikes one in every 375 African American children. But a single copy of the gene for it--two copies are necessary to develop the disorder--is carried by one in every 12 blacks, making it one of the most common genetic disorders.

The disease manifests itself only in periods of emotional or physical stress--during exercise or an infection, for example--when the body requires more oxygen. The defective red blood cells of patients with the disorder assume a sickle shape and clump together, blocking the passage of blood through small capillaries and drastically diminishing the body’s supply of oxygen. That oxygen deprivation, in turn, causes tremendous pain and organ damage, which can eventually lead to disability or death.

Aside from analgesics to control the pain and antibiotics to prevent infections, little treatment is currently available, according to Richard Leavitt of the March of Dimes Birth Defects Foundation.


The best current therapy in adults is an anti-cancer drug called hydroxyurea, which stimulates dormant genes to produce a type of non-sickling hemoglobin normally found only in fetuses. Hydroxyurea reduces the number of sickling crises, acute chest pains and hospital visits by 50% in adults.

A trial of hydroxyurea in children will be completed next year, according to Duane Bonds, who is in charge of sickle cell research at the National Heart, Lung and Blood Institute.

Although researchers are confident that hydroxyurea will be effective in children, Ohene-Frempong said, “People wonder whether it will be safe for long-term use.” The drug, like many other anti-cancer medications, can itself cause cancer in high doses. It also suppresses bone marrow development and may affect growth. “It is not a cure,” he said.

Other promising drugs, such as arginine butyrate, have also been found to be less effective than hoped, he added.

“There is a real need for new therapies,” Leavitt said.

Bone marrow transplants are a cure for some patients with the disease, according to a team led by Dr. Keith M. Sullivan of the Fred M. Hutchinson Cancer Research Center in Seattle. In the procedure, surgeons use radiation and chemotherapy to kill the patient’s bone marrow--the source of red blood cells--and replace it with marrow from a healthy donor.

Sullivan’s team reported on 22 severely ill patients who received such transplants. Two years after the operations, 16 were free of sickle cell symptoms, four had rejected the donor tissue and two had died. Ohene-Frempong estimates that about 50 children have received such transplants in the United States and another 100 in the rest of the world.


But the procedure can be dangerous. In addition to the risk of death from infection during the procedure, patients run an increased risk of cancer and loss of fertility years after the transplant. For this reason, physicians reserve it for patients who have suffered a stroke or who have severe organ damage or lung complications.

Perhaps the major limitation is that patients must also have a compatible sibling donor. Consequently, only about 7% of sickle cell victims qualify for the procedure.

Researchers have greater hope for the unusual approach to gene therapy revealed last week by Kmiec. Most gene therapy studies involve inserting a healthy form of the defective gene into the patient to produce a protein that is missing in the disease. Kmiec induces the patients’ cells to heal themselves.

The key is an artificially constructed short chain of DNA and RNA that researchers dissolve in fat globules that carry it into the cell. The DNA--deoxyribonucleic acid, which encodes the blueprint of life--binds to the defective region of the gene and indicates what repairs should be made. The RNA--ribonucleic acid, which normally serves as an intracellular messenger for genetic information--apparently stabilizes the chain so it is not rapidly destroyed.

Although Kmiec does not know precisely how the process works, the artificial DNA/RNA binds to the defective gene--in effect acting like a neon sign that tells the cell’s own repair machinery that it needs fixing.

The Thomas Jefferson team reported last week that it had removed blood cells from a sickle cell patient and treated them with the new procedure. Between 20% and 30% of the treated cells were then found to have the healthy form of the hemoglobin gene. Kmiec estimated that this degree of repair would provide sufficient normal hemoglobin to alleviate symptoms.


To be an effective therapy, however, Kmiec says the procedure will have to be performed on stem cells, the bone marrow components that produce blood cells. Preliminary results from his lab indicate that such cells can be repaired as effectively as blood cells, he noted, and the team hopes to begin treating patients in 1997.

For more information: Sickle Cell Disease Assn. of America, (800)421-8453; March of Dimes Birth Defects Foundation, (800) 367-6630.


New Approaches for a Cure

Bone marrow transplants have been successful, but they are reserved for the sickest patients and as many as 10% of patients die. Researchers hope to begin trials of gene therapy next year.


Bone Marrow Transplant

1. Physicians use chemicals and radiation to kill the patient’s own bone marrow, the source of blood cells.

2. Bone marrow from a healthy donor is infused into the patient.

Gene Therapy

1. Physicians extract some of the patient’s bone marrow.

2. Outside the body, it is treated with a DNA/RNA fragments, dissolved in fat globules to get them into cells, which corrects the genetic defect.

3. The marrow is infused back into the patient.