Scary Cure

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It’s hard to imagine asking a doctor to destroy a part of your brain. For the 1.5 million Americans suffering from Parkinson’s disease, however, such a drastic measure–in which an electrode is used to kill tremor-causing neurons–may occasionally be necessary.

The irreversible procedure is just one of many therapies, both surgical and pharmacological, Parkinson’s patients have tried over the years to control the tremors, rigidity and other symptons that characterize the disease. All of the treatments offer some relief, but none can remotely be called a cure. Now that may be changing. The deeper scientists peer into the human genome, the more they’re uncovering the secrets of Parkinson’s–and the more they’re growing convinced that next-generation drugs may be at last be able to beat back the disease. What’s more, the benefits may not be limited to Parkinson’s, but may also be used to treat Huntinton’s, Lou Gehrig’s and even Alzheimer’s disease–all of which have similar neurochemical roots and could respond to similar drugs. Says neurobiologist Michael Zigmond of the University of Pittsburgh: "A breakthrough in any of these diseases could have an impact on the others."

The first place to look for causes and treatments of Parkinson’s disease is in the brains of patients themselves. As the illness worsens, brain tissue becomes clogged with a protein muck that includes a substance called alpha-synuclein. No one knows exactly what alpha-synuclein does, but it’s believed to play a role in the smooth transmission of nerve signals. When the substance clumps, it can’t do the work it was designed to do, leading to neuron damage, loss of the neurotransmitter dopamine, and eventually to the familiar shakiness of such well-known Parkinson’s sufferers as Janet Reno and Muhammed Ali.

The hunt for a Parkinson’s cure got a boost in 1997, when researchers discovered a tiny population of patients who have a mutant gene that codes for alpha-synuclein. This might seem like open-and-shut evidence that the cause of the illness had been found, except that the vast majority of Parkinson’s patients, whose brains also grow gummed up, do not carry the mutation. Still, scientists are convinced that the bad gene is a powerful clue. "There appear to be more clumps in the brains of people with the mutant gene," says Zigmond. "Learning how the protein functions may help us develop drugs that target it."

Another gene, newly dubbed the parkin gene, has also been getting a lot of attention. In 1998, Japanese researchers were studying a young patient with early-onset Parkinson’s and found a recessive gene that appeared to be associated with the disease. Though relatively rare, the parkin gene is much more common than the defective alpha-synuclein gene, and in places like China, with high rates of early-onset Parkinson’s, it may play a role in up to 20% of cases. Just last October, researchers at Duke University went a step further, discovering a previously unseen mutation on the parkin gene that appears to link it to late-onset forms of the disease as well. "Once we figure out how that gene functions," says neurology professor Ira Shoulson of the University of Rochester Medical Center, "we could perhaps disrupt it pharmacologically."

Just as important as protecting healthy neurons is repairing or replacing nerve cells that have already been damaged. The body produces a whole bath of trophic–or growth–factors, that help neurons and other cells develop. If the brains of Parkinson’s patients could be fortified with additional trophic doses, many scientists believe, damaged neurons might be reawakened or repaired. While there is some thought in the medical community about engineering genes to churn out the substances, the pharmaceutical industry is taking a more direct approach.

Currently, Guilford Pharmaceuticals in Baltimore and Amgen in Thousand Oaks, Calif., are collaborating on a synthetic neurotrophic compound that can be taken orally and then travel to the brain, where it bonds with proteins in dopamine neurons. The tricky part is that most trophic molecules are too big to cross the blood-brain barrier, so Guilford and Amgen are working on a smaller one that can get where it needs to go. The progress so far is promising. "We’re in phase two human trials and the study is going very well," says Dr. Craig Smith, an M.D. and the president of Guilford. "If the drug proves safe and extremely effective in trials, it could be on the market as early as 2005."

Whether such an anti-Parkinson’s potion is really so close at hand is unclear, but scientists are not waiting to find out. Other possible treatments now under study include boosting anti-oxidants, which would protect brain cells from free radicals, highly reactive molecules that are byproducts of oxidation; and blocking the body’s production of compounds called excitatory amino acids, which can sometimes cause neuron damage. It’s hard to say which, if any, of these treatments will likely succeed, but with science closing in from so many directions, it’s possible that Parkinson’s disease–for the first time–may find itself on the run.