The Race for a Cure

Basic Science Research
A-T has always been an enigma. The physiological and molecular bases of the disorder have remained a mystery despite years of research examining various aspects of the disease. Until scientists understand the basic problem of pathology of A-T, they cannot develop more effective ways to treat the patients. Therefore, the key to understanding A-T lies in figuring out how one defective gene causes so many different symptoms.

In June of 1995, Dr. Yosef Shiloh’s laboratory in Israel, working with many other research labs, isolated the gene that causes A-T. Ever since that time, more and more scientists around the world have become interested in A-T and are conducting many new studies to help figure out this brutal disease.

We now know that the A-T protein (ATM) sends an important signal to several different systems working in our cells by modifying other proteins, and consequently activating or inactivating them. In other words, the A-T protein tells other proteins in the cell that they should work harder, or perhaps stop working for a while, and so it modulates the life cycle of the cell. Researchers have also determined that the "trigger" that causes the A-T protein to start doing its job is when DNA has been damaged in a certain way by radiation, chemicals or cellular metabolites. Therefore, the A-T gene is part of a signaling system that alerts the systems controlling the life cycle of the cell by saying, "Attention! Damage has been caused, slow down your growth and wait until it’s repaired."

Scientists are now beginning to understand how the ATM protein is activated or turned on following damage to a cell’s DNA. This knowledge has long been sought after. In addition, new ATM interacting proteins continue to be identified. Researchers are using various techniques, collectively known as proteomics, to find the other proteins that interact with ATM. Identification of these proteins could have some big implications; for example, if the genes that make the other proteins were damaged, they could cause diseases that look very much like A-T. Importantly, research such as this may also lead to the identification of therapeutic targets for A-T.

Animal Models

Several laboratories have developed "knock-out" mice that have both copies of the A-T gene damaged (they are called "knock-out" because scientists have disrupted or "knocked out" the mouse A-T gene in an attempt to mimic the human condition). These knock-out A-T mice show many of the same symptoms that we see in A-T patients. Pharmacologists and neurobiologists are trying numerous drugs and medical interventions on the A-T mice in hopes of finding a strategy that might help to slow the disease’s progression in A-T patients. In addition, one researcher is developing several different genetic strains of ATM knock-out mice in order to identify genes that may modify the severity of A-T.

The A-T Children’s Project is also funding the development of new large and small animal models for A-T. New large animal models, which are more closely related to humans, include the monkey, cow, and pig. Small A-T animal models, which can be used for the systematic screening of therapeutic drugs and compounds, are also being developed, and include the fruit fly and zebrafish.

Search for Treatments

The A-T Children’s Project continues to fund research in areas that include:

Gene Therapy: Researchers are starting to test the efficacy of their gene therapy protocols in mice, and are simultaneously developing a new gene therapy protocol for A-T which would allow for stable, long-term expression of the ATM protein.

Neural Stem Cells: Scientists have demonstrated a significant therapeutic effect by using neural stem cells in a mouse that has a pattern of neurodegeneration similar to A-T.

Bone Marrow Transplantation: Significant progress is being made by researchers who are developing a successful bone marrow transplantation protocol in mice with A-T. They will now begin to test how effectively this protocol prevents immune abnormalities and immune-related cancers in these mice.

Antioxidants: Several researchers are investigating the therapeutic effects of super-antioxidants in A-T cells and mice, with positive results thus far.

High Throughput Drug Screening: Testing methods are being developed that will help researchers screen large numbers of already-approved drugs as well as new compounds to see if they are useful for treating A-T.