Gene Therapy Appears to Cure Myeloid Blood Diseases In Groundbreaking International Study

Friday, March 31, 2006

CINCINNATI -- An international group of scientists has successfully used gene therapy to treat two adult patients for a disease affecting myeloid cells. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the myeloid system.

Myeloid refers to a nonlymphocytic group of white blood cells. As a whole, myeloid disorders are common and include a variety of bone marrow failure syndromes. Acute myeloid leukemia, for example, is the most common leukemia in adults and the second most common leukemia in children. It also has a significantly worse prognosis than other leukemias.

The study was conducted by researchers in Germany, Switzerland, England and the United States. Scientists at Cincinnati Children's Hospital Medical Center were involved in the analysis of the study but were not involved in the clinical trial. The study "shows how to cure a whole category of diseases," says Christof von Kalle, MD, adjunct associate professor in the Division of Experimental Hematology at Cincinnati Children's and a corresponding author of the study.

In the study, physicians treated two adult men with gene therapy. These men had X-linked Chronic Granulomatous Disease (X-CGD), an immunodeficiency caused by the lack of the gp91phox enzyme. To treat this disorder, the scientists used retroviral vectors to carry the gene encoding the missing protein into the genome. At first, the vectors were randomly distributed throughout the genome. But then something unexpected happened.

"All of a sudden we started finding more and more cells where vectors were sitting next to one of three genes," says Dr. Kalle. "Not only did these genes get switched on, but gene-corrected blood cells began to grow and, as a result of the gene therapy, they tripled. So the activation of these three genes actually -- and unexpectedly thus far -- boosted the performance of the gene therapy. Moreover, it appears to have done so without causing any negative side effects so far, which occurred in gene therapy trials in France a few years ago."

Those earlier gene therapy studies in lymphoid cells had succeeded in correcting genetic diseases of the blood, but a leukemia-like disease developed in three children who had participated in gene therapy trials in Europe in 2002. Studies by Dr. Kalle revealed that the virus vector carrying the therapeutic gene had inserted close to a cancer-related gene called LMO-2 and activated it. The activation of the LMO-2 gene resulted in the leukemia. Of the 28 children treated in these earlier European gene therapy trials, 24 are considered cured of the disease by gene therapy.

In this new Phase I study, the correction of gp91phox function led to formation of chemical compounds needed for white blood cells to kill bacteria. The two patients participating in this trial are doing well clinically, are no longer taking daily antibiotics, and granulocytes in their blood are killing bacteria and fungi, according to Manuel Grez, MD, a physician at the Institute for Biomedical Research in Frankfurt, Germany, and a corresponding author of the study.

A third patient with X-CGD also has been treated with gene therapy, but results in that patient, although positive, have not been published. Researchers in the Division of Experimental Hematology at Cincinnati Children's have focused considerable effort at finding and understanding how to improve gene therapy and avoid side effects. In addition to several trials ongoing at Cincinnati Children's, the program is carrying out active international collaborations with scientists in England, France, Italy, Switzerland and Germany.

"Based on this study and prior studies in severe combined immunodeficiencies, it is very clear that gene therapy approaches will succeed in treating some devastating genetic diseases in children," says David Williams, MD, director of Experimental Hematology and associate chairman for translational research at Cincinnati Children's. "In this way, gene therapy is just beginning to fulfill some of the predictions made in the 1980s and early 1990s. However, researchers still have much to learn, and the technology clearly needs ongoing improvements."

In addition to Dr. Grez and Dr. Kalle, the study was conducted by Marion Ott, MD, and Dieter Hoelzer, MD, in Frankfurt; Reinhard Seger, MD, at University Children's Hospital in Zurich; and Adrian Thrasher, MD, at the Institute of Child Health in London.

Cincinnati Children's is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health.

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Jim Feuer, 513-636-4656,