Insight

Fall 2004

Rare Disease Causes Researcher to Push Boundaries

Dr. Mike Weil doesn’t treat patients. He doesn’t develop drugs or new therapies. He doesn’t diagnose illnesses or improve life expectancies. What he does is make many of these things possible. As a mouse geneticist, he is dedicated to developing mouse models that enable researchers to study diseased and normal systems, test drug and other therapies, and look at ways of improving diagnostic tools, including bio-markers for earlier detection and treatment of disease.

As a member of the faculty of the Department of Environmental and Radiological Health Sciences, a substantial portion of Dr. Weil’s research work revolves around the Cancer Biology Group’s NASA grant. But he is involved in other projects that may have a more immediate impact on breast cancer research and on those battling a rare disease known as ataxia-telangiectasia (A-T).

“A-T is a fatal disease that usually causes death in children by their early teens, mostly because of the neurodegeneration attributed to the disease,” said Dr. Weil. “What we are working on now is the development of an animal model that will display neurodegeneration, a trait essential to our ability to test drugs that may be therapeutic for victims of A-T.”

A-T is a “recessive” genetic disease because children must inherit a defective gene from each of their parents to develop the disease. Children with A-T appear normal at birth but begin to show the fi rst signs of the disease in the second year of life, including poor balance and slurred speech caused by a lack of muscle control (ataxia). The cerebellum progressively degenerates, leading to a general lack of muscle control. Other symptoms include tiny red “spider” veins (telangiectasia), immunodeficiency with recurrent respiratory infections, a predisposition to cancer, and an extreme sensitivity to radiation (A-T children with cancer cannot tolerate therapeutic radiation). Currently in the United States, approximately 600 individuals are afflicted with A-T.

Part of Dr. Weil’s work involves genetically engineering a mouse that has a lifespan long enough to develop the neurodegeneration that is a hallmark of the disease but to date has not been replicated in the mouse model. Dr. Weil and his colleagues currently are developing a “conditional knock-out” mouse model using specialized genetic engineering approaches that allow the mice to be completely normal, except for the brain (normal immune systems, normal physiological structure, etc.). These studies include three distinct populations: normal mice, mice that have one germline mutation (ATM heterozygosity), and mice with homozygous ATM mutations that will develop clinical A-T.

“If we are successful in developing this model, we then will have the opportunity to test different therapeutic drugs that may help slow the progress of A-T or improve the quality of life for those suffering from A-T,” said Dr. Weil. “While this is a rare disease, it is devastating to those families with children who are afflicted.”

Dr. Weil notes that while A-T is not a public health issue because of the rarity of the disease, there is a connection between A-T and the risk of developing breast cancer that piqued his initial interest in the disease and definitely represents a public health issue. Mothers of children who have A-T have been reported to be at an increased risk for development of breast cancer. Dr. Weil and his colleagues wanted to know if women who carried a single defective A-T gene would be at a higher risk for breast cancer, especially given the susceptibility of A-T patients to radiation exposure. Previous studies by Dr. Weil’s research group show that mice with a single defective copy of the A-T gene are susceptible to radiation-induced ductal dysplasia, a precursor to breast cancer.

“We began investigating this link, and our research showed that patients with breast carcinomas were more likely to have a variant in the ATM gene,” Dr. Weil said. “We are just starting to explore the link between the ATM gene and relative risk of breast cancer, but it is an area that definitely needs additional studies.”

Dr. Weil’s breast cancer work – in conjunction with researchers at the University of Texas M.D. Anderson Cancer Center and the Center for Genome Information, Department of Environmental Health, University of Cincinnati – is sponsored by the Department of Defense Breast Cancer Research Program, the Cleberg Fund for New and Innovative Research, and the American Cancer Society. The most recent findings on the link between A-T and increased breast cancer risk were published in Cancer 2004; (100:1345-51 2004 American Cancer Society). His work on A-T is funded by the Ataxia-Telangiectasia Children’s Project. You can learn more about A-T at the organization’s Web site, www.atcp.org.