Beyond Dopamine: The Search for Disease-Stopping Parkinson’s Drugs
The Search for Disease-Stopping Parkinson’s Drugs

by Jim Schnabel

December, 2011

Levadopa was something like a miracle drug for Parkinson’s patients when it first came into use in the late 1960s. Taken in a pill, it could pass from the bloodstream into brain tissue, where natural enzymes converted it to dopamine. By restoring dopamine levels in movement-regulating brain regions, levadopa temporarily alleviated the classic Parkinsonian motor symptoms of tremor and rigidity.

Almost a half-century later, levadopa is still the mainstay of Parkinson’s treatment, and although other dopamine-replacement drugs and surgical techniques are in use, they reduce symptoms rather than stop the underlying disease. Yet we now know that the disease spreads through the brain, ultimately reaching the cortex and causing dementia. Even our symptom-alleviating strategies that work well early in Parkinson’s disease tend to lose their effectiveness over time.

And so, somewhat belatedly, researchers are developing what they hope will be the first generation of true disease-modifying drugs for Parkinson’s. “There is a large effort underway now,” says Tim Bartels, a Parkinson’s researcher at Brigham and Women’s Hospital in Boston, part of Harvard Medical School. “But compared to Alzheimer’s disease, we are something like 10 to 15 years behind.”

Targeting Alpha-synuclein

Comparisons between Parkinson’s and Alzheimer’s are common, in part because both diseases are marked by the spread of apparently toxic clumps of protein. In Parkinson’s that protein is alpha synuclein (AS)—a neuronal protein, normally involved in cell-to-cell communication, which somehow forms aggregates inside disease-affected neurons. Some AS aggregates are large enough to be visible under a microscope, and are called Lewy bodies or Lewy neurites. Others, known as oligomers, are made of only a few copies of AS, and are much harder to detect. All these aggregates grow and, in effect, self-replicate, by attracting other copies of AS in the vicinity. They may impair the functions of neurons simply by taking up too much space, but a leading hypothesis now is that some of the AS oligomers are toxic.

Cells have powerful “garbage disposal” mechanisms that normally keep unwanted protein aggregates from piling up. But advancing age, certain genetic mutations, and/or exposures to certain enviromental toxins may weaken those disposal mechanisms, leading to uncontrolled AS aggregation and Parkinson’s. Therefore one strategy is to artificially boost these disposal mechanisms, so that they keep AS aggregation under control and thus stop the disease process. Proteostasis Therapeutics and Link Medicine, both of Cambridge, Masss, are among the companies now developing drugs to do this.

The lead compound developed by Link Medicine, for example, is meant to boost a cellular process known as autophagy, in which cells digest unwanted aggregates in a stomach-like sac filled with protein-cleaving enzymes and acids. The drug seems to have performed well in animal tests and initial human safety tests, and Link’s researchers now are trying find ways to persuade the deep-pocketed pharmaceutical industry to back expensive human clinical trials. “The perception of risk is extremely high, and Parkinson’s research is being tarred with the disappointing results of recent Alzheimer’s trials,” says Link’s founder Peter Lansbury, also a professor of neurology at Harvard Medical School. He and his colleagues hope to attract pharma backing with further small studies, for example to establish that their compound reduces AS levels in human brains.

A related idea is to find “chaperone” drugs that bind to AS proteins in their healthy form, in a way that keeps them from clumping together into harmful aggregates. A recent finding may have clarified this task. Researchers had long assumed that the healthy, functional, “native” form of AS is a single copy of the protein. But Bartels and his colleagues in the laboratory of Harvard neurologist and Dana Alliance for Brain Initiatives member Dennis Selkoe reported in Nature in August that native AS is in fact a four-copy oligomer—a “tetramer.”

“A new strategy, then, would be to stabilize this tetrameric structure we found,” says Bartels. Drugs are already being developed to stabilize native tetramers of a different protein, known as transthyretin, whose harmful aggregates cause a variety of cardiac and neurological conditions. “We are planning to test out some of these compounds to see if they stabilize native AS tetramers too,” Bartels says.

A Parkinson’s Vaccine

Active, immunizing vaccines and “passive” infusions of antibodies that target amyloid beta protein are now in clinical testing against Alzheimer’s disease, and a number of labs—including those that developed the first Alzheimer’s vaccines—have been working on active and passive vaccines against AS in Parkinson’s disease, too.

In principle, anti-AS antibodies would reduce the levels of the protein available for aggregation, either by removing AS directly from brain tissue, or simply by decreasing AS levels in the bloodstream, creating a low-concentration “vacuum” that enhances AS’s natural rate of clearance from brain to blood.

One of the more visible Parkinson’s vaccine efforts is underway at the University of Texas Health Science Center at Houston, where Chuantao Jiang, Rowen J.-Y. Chang, and their colleagues have been developing active and passive vaccine strategies. “Right now we are trying to isolate monoclonal antibodies against AS, and then apply to mice to see if this passive immunotherapy can work better than an active vaccine,” says Jiang.

One of the problems that his and other labs have faced is the lack of a good AS-based mouse model of Parkinson’s. Current lines of mice that have been genetically engineered to overexpress AS or to express mutant forms of AS tend to vary in their levels of neuronal AS production and disease signs, making it hard to show consistent results for any anti-AS therapy—and thus making it hard to justify human trials. But there are now reports in the field of a much-improved AS-based Parkinson’s mouse model that is about to be published. “We are looking forward to using it,” says Jiang.

Helping Mitochondria

Several lines of evidence suggest that the Parkinson’s disease process kills vulnerable neurons mainly by damaging their mitochondria—the tiny, oxygen-burning reactors that produce chemical energy in cells. Certain mitochondrial toxins, such as the pesticide rotenone, selectively damage the same midbrain dopamine neurons that are affected in Parkinson’s; these toxins are even used to create animal models of the disease. Moreover, some of the gene mutations linked to familial Parkinson’s disease appear to exert their harmful effects by impairing mitochondrial function.

Clemens Scherzer, a neurologist at Brigham and Women’s Hospital, recently found another clue that implicates mitochondrial vulnerability in the disease:  A group of genes that control mitochondrial and related energy-production functions turn out to be expressed at abnormally low levels in the brain cells of people with Parkinson’s, even at early stages of the disease process. How this impairment of function relates to toxic AS aggregates and the overall disease process isn’t yet clear. But Scherzer and his colleagues have found evidence that restoring the expression levels of these genes to normal, via their master regulator gene, PGC-1α, may help brain cells resist Parkinson’s-related stresses. “We’ve shown in cell cultures that if you increase PGC-1α activity, you can block the toxicity of alpha synuclein or rotenone,” says Scherzer.

The next step is to find PGC-1α boosters that are promising enough to take into animal and eventually human testing. “We’ve developed a high-throughput gene expression screen for drugs that activate PGC-1α function, and with this we hope to get some candidate drugs that we can test in animal models,” Scherzer says.

Boosting Urate

Population studies have turned up a number of environmental factors or biological markers linked to Parkinson’s risk. Pesticide exposure, for example, is linked to a higher risk. Coffee drinking and tobacco smoking are linked to a lower risk. But the factor that seems most strongly associated with a lower Parkinson’s risk is urate—humble uric acid—a byproduct of the digestion process and a major constituent of urine.

In 2008, a team led by Alberto Ascherio, a professor of epidemiology and nutrition at the Harvard School of Public Health, found that participants in a large health study who had a high-urate diet were significantly less likely to develop Parkinson’s during the study’s 14-year monitoring period. “Those in the top 20 percent of estimated serum urate had a 50 percent lower risk of developing Parkinson’s” compared with those in the lowest quintile, says Ascherio. The following year Ascherio, with Harvard neurologist Michael Schwarzschild and others, followed up by finding that higher urate levels in early-stage Parkinson’s patients were associated with slower disease progression—a finding they confirmed with a further study this year. “I don’t think there is any other marker that has such a strong association with disease risk and progression,” says Ascherio.

Urate is a powerful antioxidant, and thus may reduce the high stresses from hydrogen peroxide and other oxygen “free radicals” inside neurons affected by Parkinson’s. In principle, a person could raise urate levels by adjusting his or her diet, but the organic compound inosine, which is already used as a nutritional supplement, offers a more straightforward and controllable way to boost bloodstream urate levels. (Too much urate would cause the medical condition known as gout.)  Schwarzschild, Ascherio and their colleagues have begun an initial safety trial of inosine—with a dose designed to bring serum urate to the upper normal range—in about 90 early-stage Parkinson’s patients. “So far the tolerability has been very good,” says Ascherio. “If everything goes well, next summer we may be able to apply for funding for a larger trial.”