Robert Freidlander uses a brain model to explain how blocking the activity of a single enzyme may delay disease progression and eath from nervous system maladies such as Huntington's, Parkinson's and Lou Gehrig's diseases. Photo by Rose Lincoln

Huntington's disease is treacherous. Its symptoms do not usually appear before age 35. These symptoms random twitches, general clumsiness, slurring of speech, and mental deterioration become progressively worse during the next 15 to 20 years. No cure exists and the disease is inevitably fatal.

But things may change in the next few years. A way to delay worsening of the symptoms and death from the disease has been found by researchers working at Harvard University-affiliated hospitals in Boston. The successful treatments occurred in mice with a human-like form of Huntington's, prolonging their lives the human equivalent of 10 years. Researchers hope the same type of drugs may be ready for testing with humans in two to three years.

The process of brain-cell death that characterizes Huntington's also occurs in stroke, head trauma, and Parkinson's and Lou Gehrig's diseases. Therefore, similar drug treatments may well work to reduce the damage of strokes and head trauma and to delay deterioration and death in the other maladies. There is also evidence that this type of treatment strategy could work for Alzheimer's disease.

"Our results give impetus to other researchers and drug companies to develop the first effective drug for Huntington's disease," says Robert Friedlander, leader of the experimental team and instructor in surgery. "We are also excited about the implications of this work for other diseases that share the same pathway to cell destruction."

Extending Life

Huntington's starts with the mutation of a gene that carries instructions for making a protein called, appropriately, huntingtin. No one knows the purpose of the protein in people without the disease, but in people with the malady huntingtin is cut up by an enzyme, or biological catalyst, called caspase-1. The protein fragments accumulate causing dysfunction, then death, of brain and other nerve cells.

Friedlandler's group at Brigham and Women's and Massachusetts General hospitals tested the idea that by blocking caspase-1, the onset of Huntington's would be delayed and life would be prolonged. That idea turned out to be true.

Mice engineered with a genetic mutation that interferes with the action of caspase-1 were compared with those without such a mutation. All had a humanlike form of Huntington's.

The comparison involved a sort of log-rolling contest. Mice had to keep their balance while standing on a horizontal rod rotating between 5 and 25 times a minute. At age 9 weeks early adulthood for the rodents mice who received the mutated caspase gene stayed on the rolling rod for 10 minutes, the required duration. Those who did get the engineered gene fell off at between 1 and 7 minutes, depending on the speed of rotation.

At age 12 weeks middle age for mice those who had their caspase incapacitated were slowed down but stayed on the rotating rod between 7 and 9 minutes. Without benefit of caspase blocking, their companions fell off in 5 minutes or less.

That's very interesting, but what relevance does it have for humans?

The scientists examined donated brains from deceased people with and without Huntington's and found good evidence of a difference in caspase-1. Those with the disease clearly showed high levels of the enzyme which had chopped up their huntingtin protein and killed many brain cells. Those who were free of the malady exhibited a much lower level of caspase.

In untreated Huntington's mice, the disease began at age 77 days and killed them by age 100 days. Those who received mutated caspase-1 genes didn't show Huntington's symptoms until age 84 days and survived to 121 days. Treated mice lived about 20 percent longer than untreated, or the equivalent of 10 extra years of human life.

As a further test, the researchers injected drugs known to inhibit the activity of caspase into the brains of mice with Huntington's. They then compared their lifespan with Huntington's mice who did not receive the drug, known as zVAD.fmk. Treated mice lived about 100 days compared with 79 days for untreated animals. That also works out to a 20 percent increase in lifespan, or a human equivalent of about 10 extra years of life.

"The drug did not prolong suffering, or the terminal part of the disease, but it lengthened the useful, functional parts of their lives," according to Friedlander.

Unfortunately, drugs given to the mice are too toxic for use with humans. A number of pharmaceutical companies hope to develop safe alternatives. "A couple of companies are close," Friedlander says, "but it will be at least two years before testing on humans will begin."

James Gusella of Harvard Medical School discovered the Huntington's gene in 1993, prompting a surge of research and better understanding of the disease. A test now exists for detecting the gene, but people are reluctant to take it because no cure exists. Also, because the symptoms do not appear until the gene-carriers pass their most active reproductive years, parents can unwittingly pass the disease to their children.

"Once we have a treatment, people are more likely to be tested, and less likely to unknowingly pass on the gene," Friedlander comments.

Reducing Stroke Effects

Before his success with Huntington's, Friedlander experimented with mice bred to get a humanlike form of Lou Gehrig's disease, or amyotropic lateral sclerosis (ALS). In animals engineered so that their caspase genes are ineffective, ALS progresses more slowly and the animals survive longer than mice in whom the enzyme's activity has not been blocked.

Friedlander also showed that drugs related to zVAD.fmk reduce the consequences of stroke and head injuries. "Injecting a drug called yVAD.cho into the brains of mice after a stroke cuts the volume of brain that is damaged in half," he notes.

The fact that such drugs are not safe enough to use in humans is frustrating, says Friedlander. "I have patients calling me and begging me for a pill that can relieve some of their suffering and prolong their lives," he says. "One ALS patient volunteered to test the mouse drugs on himself. `When you have ALS, you don't care about side effects,' he said."

Experimenters injected a drug that induces Parkinson's disease into the brains of mice with and without the gene that inhibits caspase. The caspase mice survived the experience much better, indicating the potential for a better treatment than is now available for the disease.

A close relative of caspase-1, called caspase-3, seems to cleave one of the proteins involved in killing brain cells in Alzheimer's disease. Blocking caspase-3, then, may also delay the progression of dementia and death in that ailment. "I'm eager to look into this, but there are no good mouse models of Alzheimer's which would let us do the experiments we need to do," Friedlander explains.

The thing that is most exciting to us and other researchers," he continues, "is that the cause of brain-cell death doesn't seem to matter. It can be Huntington's, stroke, head trauma, or ALS. But in every case the pathway by which the cell dies is the same. If we can block that path, we might give patients more time to function better and maybe even to recover."