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Huntington’s disease is one of a number of degenerative diseases marked by build up of a malformed proteins in brain cells, mainly in the basal ganglia and the cerebral cortex. Normally, cells dispose of or recycle their waste material, including unwanted or misfolded proteins, through a process known as autophagy, or ’self-eating’.

The group of Professor David Rubinsztein, a Wellcome Trust Senior Clinical Fellow at the University of Cambridge, has previously shown that stimulating autophagy in the cells can be an effective way of preventing the malformed proteins from building up. However, there are currently no treatments available that slow the neurodegeneration in people with Huntington’s disease. Rapamycin, an immunosuppressant used to lower the body’s natural immunity in patients who receive kidney transplants, is the most promising candidate drug currently available but can have significant side effects.

Now, in research published today online in the journal Nature Chemical Biology, Professor Rubinsztein and colleagues have shown that a number of FDA-approved drugs for treatments such as migraine and hypertension are able to stimulate autophagy in fruit flies and zebrafish through unexpected pathways.

“By screening a number of drugs that have already been shown to be safe in humans, we have been able to identify some unexpected and very promising pathways involved in Huntington’s,” says Professor Rubinsztein. “In collaboration with Cahir O’Kane’s group in Cambridge and Summit Plc, we have shown that these drugs can alleviate the toxicity of the Huntington’s disease mutation in cell-based, fly and zebrafish models. The big question for us is whether they will do the same in humans.”

One of the drugs tested, verapamil, which is currently used to treat high blood pressure and heart arrhythmias (among other indications), inhibits the influx of calcium into cells which, in turn, appears to regulate autophagy. Similarly, clonidine, currently used to treat hypertension or migraine, appears to work on autophagy by decreasing levels of cAMP, a molecule that is important in many biological processes.

If the drugs can stimulate autophagy effectively over long-term periods in human brains, then they may have the potential to help delay the onset of Huntington’s disease. The candidate drugs are relatively safe and well tolerated when used to treat the diseases they were designed for. A minimal side-effect profile would be highly desirable for a drug treatment aiming to delay the onset or slow the progress of Huntington’s. Such drugs may need to be taken for decades, and even moderate side effects may discourage people from taking them over a long period.

“We know the genetics of Huntington’s disease and can predict the majority of people at risk,” says Professor Rubinsztein. “If we can find a safe, well tolerated drug, then a person at risk could be placed on a drug regime to help prevent onset. It is much easier to stop something happening than having to treat it once it has started.”

Professor Rubinsztein and colleagues will shortly begin testing the drugs in other animal models to evaluate their safety and efficacy.

Source: Wellcome Trust

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The screen relies on changes in dozens of small molecules in serum. These “metabolomic” alterations form a unique pattern in people with Parkinson’s disease, according to a team led by researchers at the Weill Cornell Medical College in New York City.

They published their findings in the journal Brain.

“A reliable blood test for Parkinson’s disease would revolutionize not only the care of people with this debilitating illness, it would facilitate research as well,” notes study senior author Dr. M. Flint Beal, chairman and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College, and neurologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

According to the National Parkinson Foundation, an estimated 1.5 million Americans have the neurodegenerative disease, and 60,000 new cases are diagnosed each year. Actor Michael J. Fox, boxer Muhammad Ali, and former U.S. Attorney General Janet Reno all suffer from Parkinson’s, which strikes men and women in roughly equal numbers.

“Right now, a Parkinson’s diagnosis is made solely on a clinical review of symptoms — we have no biologic test,” notes Dr. Beal. At best, a symptom-based screen is still only 90 percent accurate, he adds.

“That can cause real problems, because that remaining 10 percent of patients — who may have look-alike conditions such as multi-system atrophy or progressive supranuclear palsy — end up getting treated with Parkinson’s drugs,” Dr. Beal says. “These medicines may appear to help them a little while, but in the meantime, they haven’t been getting the treatment that’s necessarily best for them.”

An early-detection test would also be enormously useful in tracking the health of patients who may be at higher risk for Parkinson’s, such as those with a family history of the disease.

Finally, the integrity of clinical trials is undermined by the lack of an accurate screen, Dr. Beal notes. “Every time you do a clinical trial into Parkinson’s and you have patients that are misdiagnosed, it enters ‘noise’ into the analysis, skewing the results. A truly reliable test could help eliminate that,” the researcher notes.

That’s why encouraging results for the new test — based on a patient’s “metabolomic profile” — are so important.

Metabolomics is the study of changes in thousands of distinct, very small molecules found in body fluids or tissues. “Anytime you have a genetic or environmental perturbation, these molecules are altered in specific ways,” Dr. Beal explains.

Because Parkinson’s treatment could itself trigger some of these alterations, the researchers first compared metabolomic patterns in the blood of Parkinson’s patients who were not undergoing treatment versus those who were medicated. “That gave us a ‘medication-free’ profile that we could use going forward,” Dr. Beal explains.

In the next stage of the research, the team compared blood samples from 66 patients with Parkinson’s disease against 25 healthy controls (most of whom were the patients’ spouses). The metabolomic analysis included over 2,000 small molecules found in the blood.

“We discovered a clear differentiation between the metabolomic profiles of the Parkinson’s disease patients versus those of the controls,” Dr. Beal says. “No one molecule was definitive, but a pattern of about 160 compounds emerged that was highly specific to Parkinson’s patients.”

The significance of many individual compounds to the disease remains unknown and will be the focus of future study. But changes in a few well-known metabolites linked to oxidative stress were clearly linked to Parkinson’s. These included low levels of the antioxidant uric acid; an increase in blood levels of another antioxidant, glutathione; and increased levels of a marker for oxidative damage called 8-OHdG.

“Together, these and other compounds were arranged into a metabolomic pattern that identified Parkinson’s disease with great accuracy,” Dr. Beal says.

He stressed that more work needs to be done to validate the finding, and a test that might be used routinely by doctors is still a few years away.

“We are currently enlarging the sample size and studying people at serial intervals, to see if this test might also serve as a benchmark for disease progression,” Dr. Beal says. “We are also looking at people who carry a gene for a familial form of Parkinson’s, but who do not have the illness now. We hope to track them over time to see if this metabolomic profile is predictive of disease onset.”

If those data prove as promising as this early trial, an early-detection blood test for Parkinson’s disease could someday become a reality. According to Dr. Beal, “That would be a big step forward for both the treatment and the study of this devastating illness.”

This work was supported by the Michael J. Fox Foundation, the Department of Defense, and Edwin and Carolyne Levy.

Co-researchers include lead researcher Dr. Mikhail Bogdanov, of Weill Cornell Medical College and Bedford VA Medical Center, Bedford, Mass.; Dr. Wayne R. Matson, of Bedford VA Medical Center; Dr. Lei Wang, of Weill Cornell and Bedford VA Medical Center; and Dr. Rachel Saunders-Pullman and Dr. Susan S. Bressman, of Albert Einstein College of Medicine, New York City.

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