By David N. Leff

By the age of 10, a child born with ataxia-telangiectasia is likely to be wheelchair-bound. Paradoxically, this whole-body-devastating affliction holds a prospect of treating other children with pediatric brain tumors.

Ataxia-telangiectasia (A-T) is a rare, inherited, fatal disease. Only about 500 cases have been diagnosed in the U.S. It occurs once in 40,000 live births. Death intervenes in a patient's twenties.

Scientists around the world actively interested in A-T may not quite outnumber the diagnosed cases, but their engagement goes beyond attempts to treat the disease.

The gene on which they focus is called ATM — "ataxia-telangiectasia mutated." It lurks on the long arm of human chromosome 11, and expresses ATM, one of the body's largest proteins — 350 kiloDaltons in atomic mass.

"ATM is involved in the normal functioning of all of the systems that are defective in A-T," observed molecular neurobiologist Peter McKinnon. "One of the things that make A-T so interesting," he told BioWorld Today, "is that it covers a lot of biology's research subdisciplines — from cancer to cell-cycle to neurophysiology.

"Ataxia — uncoordinated movements and loss of fine motor skills — are usually the first hallmarks of A-T," McKinnon recounted. "By the time patients are about ten years old," he went on, "they are unable to walk, and usually confined to a wheelchair. In addition to the slow degeneration of their central nervous system, A-T patients have immune deficiencies, are prone to develop cancer and sensitive to ionizing radiation. So far," McKinnon observed, "the reason a single defective gene leads to such a variety of problems is unknown."

An assistant member of St. Jude Children's Research Hospital in Memphis, Tenn., McKinnon is senior author of an article in the current issue of Science, dated May 15, 1998. Its title: "Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system."

"What we wanted to do," he recounted, "was make a mouse model of A-T, to investigate the consequences of knocking the ATM gene out on the nervous system. Because ATM is known to be involved in the radiation response pathway in human radiation sensitivity disease, we used radiation to activate the pathway in the nervous systems of these knockout mice." (See BioWorld Today, Nov. 25, 1996, p. 1, and July 12, 1996, p. 1)

Decades ago, radiation oncologists noted that when they treated A-T patients with cancer, the conventional radiation doses left them with life-threatening after-effects similar to much higher doses.

Outcome 'Totally Unexpected'

"Because A-T is a neurodegenerative disease," McKinnon continued, "it seemed likely that we might identify a susceptible population of neurons that would reveal some information about the progression of the disease.

"What we found was completely the opposite — and totally unexpected.

"In certain populations of their developing brains, these cells did not die. Unlike the neurons in normal mice, they were very, very resistant to radiation-induced cell killing. It was paradoxical, because here you have this disease that ostensibly leads to neuronal loss. And what we found instead is that when you activate the pathway — which is presumably what happens in the disease — the neurons don't die."

This radiation-resistance led McKinnon and his co-authors to suggest that "in fact what ATM was doing was acting as a developmental survival monitor for neuronal damage, to prevent an organism from developing with faulty neurons.

"So we think," he went on, "that ATM is like a checkpoint or guardian of the developing nervous system, such that if it's not there, you've created a nervous system with damaged neurons. These subsequently malfunction, and then you get the degeneration that happens in A-T."

This just-discovered role in the mutant ATM protein's resistance to radiation led McKinnon to observe that "pediatric brain tumors are often treated with radiation. One of the unfortunate consequences of that is that you kill normal non-cancerous brain cells, thus causing neurological dysfunction later in life." He foresees "the possibility of using a mutated ATM to protect that normal tissue during radiotherapy."

He pictures, when this becomes feasible, "using something like viral-mediated gene transfer, something with a gene therapy approach."

Looking Over Horizon To Treat Other Ills

"When you broaden the view," McKinnon continued, "and start to look at diseases like Alzheimer's and Parkinson's, you begin to see the potential for modulating this apoptotic response. Then you would have possible therapeutic benefit for other, nonrelated neurodegenerative pathways.

"One of the more interesting aspects of our Science paper," McKinnon mentioned, "is that it is among the first solid demonstrations that ATM functions in the nervous system. Clearly," he pointed out, "it's critical to normal nervous system development and maintenance. Because if you don't have it, you're in a wheelchair by the time you're 10 years old."

McKinnon doubts, however, that radiation is likely to be the agent that activates an A-T pathway in humans. "Now we have an assay to start to investigate in a rational way the normal physiological signaling mechanisms that may be important in the human disease.

"What we've found is that normal ATM is required when there is excessive damage to the neurons, to initiate a biochemical cascade that will lead to apoptosis — programmed cell death — to eliminate damaged neurons. If that doesn't happen when it should, then you're going to build a nervous system that has damaged components. If that happens, then there is going to be a subsequent price to pay for having these damaged cells in the nervous system.

"That is where you start to see the neurodegeneration. The initial insult doesn't get rid of the cell when you have ATM there. And these cells ultimately die because of the damage they've accumulated. So now they are part of the mature nervous system, and they should have been eliminated during development.

"The nervous system," he explained, "uses apoptosis to help form during development. It's also a normal process, the elimination of neurons. It makes many more cells than it needs, and then pares them down to have what it wants." *