Public release date: 10-Feb-2011 [ | E-mail | Share ] Contact: Carrie Bebermeyerbebermcl@slu.edu314-977-8015Saint Louis University

ST. LOUIS ? in new research from Saint Louis University, investigators have found evidence that a toxin produced by the brain is responsible for the series of cellular events that lead to Parkinson’s disease. the study, published in PLoS One, found that the brain toxin DOPAL plays a key role in killing the dopamine neurons which trigger the illness.

In earlier research, Saint Louis University investigators found that DOPAL seemed to be responsible for killing healthy dopamine cells, which in turn causes Parkinson disease to develop. Now, research in an animal model gives them further reason to suspect the chemical as the culprit.

Parkinson’s disease is a debilitating neurodegenerative movement disorder, affecting 2 percent of individuals older than age 65 and 4 to 5 percent older than 85 years. the disorder is due to a loss of dopamine neurons and is characterized by bradykinesia and tremors while at rest.

Saint Louis University investigators found that DOPAL, a breakdown product of dopamine, killed healthy dopamine cells and produced an animal model of Parkinson’s disease, giving them evidence to suspect that DOPAL is the culprit.

Dopamine, a vital chemical that allows for coordinated function of neurons controlling the body’s muscles and movements, is produced by nerve cells in the substantia nigra. when 80 percent of these cells die or become damaged, symptoms of Parkinson’s disease begin to appear, including tremors, slowness of movement, rigidity and stiffness, and difficulty with balance.

Lead researcher, W. Michael Panneton, Ph.D., professor of pharmacological and physiological science at Saint Louis University School of Medicine, says the research offers a big step forward in the understanding of Parkinson disease.

“In Parkinson disease, we knew that the death of dopamine cells is responsible for patients’ symptoms,” said Panneton. “But no one knew why the cells are dying.”

From a cellular perspective, doctors know some pieces of the puzzle. they know that Parkinson patients have a loss of dopamine neurons in a part of the brain called the substantia nigra, leading to severe dopamine loss in another part of the brain called the striatum, and the aggregation of a protein called alpha-synuclein.

Alpha-synuclein is found throughout the brain. in some people, the protein clumps together. Researchers found that it is DOPAL that causes alpha-synuclein protein in the brain to aggregate. This induces further increases of DOPAL leading to the death of the dopamine-producing cells, which in turn causes Parkinson’s symptoms to develop.

Currently, the main approach to Parkinson’s disease is to treat symptoms by replacing dopamine that’s lost when the cells die. This approach however does not prevent the loss of dopamine neurons causing Parkinson’s disease.

This new research opens up promising new research avenues to prevent dopamine neuron loss and the progression of Parkinson’s disease.

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The research was funded by Saint Louis University School of Medicine.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. the school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

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Karuna has two novel programs in development, Harrigan said, and has been incubating at the Boston firm PureTech Ventures, whose partner, Eric Elenko, was in charge of day-to-day operations before Harrigan took over. Karuna’s founding team also includes PureTech associate Andrew Miller.

Elenko and Harrigan declined to reveal specifics but said one of the firm’s molecules with a novel mechanism for treating schizophrenia is being tested in humans.

Earlier in his career at Pfizer, Harrigan played a key role in the development of the antipsychotic pill ziprasidone (Geodon).

Karuna’s lead drug is making progress, Harrigan said: “We have clinical evidence in the target population that, using the standard measurement for symptoms of psychosis in patients with schizophrenia, there is significant improvement.’’

In true PureTech fashion, Karuna is building a team with top names in pharma and academia. Steven Paul, former president of research at Lilly, is the start-up’s chairman and a scientific adviser. The scientific advisory board includes Joseph Coyle, a professor of psychiatry at Harvard Medical School; Jeffrey Conn, a professor of pharmacology and director of the drug discovery program at Vanderbilt; Anthony Grace, a professor of neuroscience, psychiatry, and psychology at the University of Pittsburgh; and Carol Tamminga, a psychiatric researcher at the University of Texas Southwestern.

Karuna has not raised money from outside investors, Elenko said. It is largely a virtual operation. Harrigan still lives in the new London, Conn., area, and the company is using contract research facilities and talent.

Sometimes it takes a parent’s perspective to understand what is really at stake for patients.

And two parents of children with cystic fibrosis, a genetic disease, say the regulators got this one wrong.

“I appreciate that they are trying very hard not to do anything bad, but the measures that they were asking us to use for this particular product were meaningless,’’ said Francine Healey, a Needham mother of two children with cystic fibrosis.

Cystic fibrosis, which causes a buildup of mucus in the lungs, also affects digestion and the ability to absorb nutrients. about 30,000 Americans have the disease, and they have a median life expectancy of 37 years.

Liprotamase — the Lilly drug that it picked up through its buyout of Alnara Pharmaceuticals of Cambridge — is intended to provide certain pancreatic enzymes that patients with the disease and other conditions need to get nutrition from food.

Yet the FDA panel voted 9 to 3 that there was not enough evidence the drug is effective.

The FDA is expected to say by mid-April whether it will take the panel’s advice.

Healey’s 19-year-old son and 16-year-old daughter take digestion supplements made with enzymes from pigs. Liprotamase is made in a microbial process and would be the first approved treatment of its kind not to use the pig enzymes.

FDA staff noted that liprotamase scored lower in a measure of fat absorption than the existing supplements made with pig enzymes.

Patrick Marshall, whose daughter has cystic fibrosis, said the fat absorption measure has never been an important one for his daughter.

He would leave it to her doctor to decide whether she should take liprotamase instead of the pig-derived supplement.

The nonprofit Cystic Fibrosis Foundation has funded development of liprotamase, in part because of concern that sick pigs could contaminate or limit the supply of supplements.

Both Healey and Marshall have been fund-raisers for the foundation.

Lilly might have to make a tough decision about whether to invest in another clinical trial of liprotamase, depending on the FDA’s ruling. The company said it is confident in the clinical trial data that has been submitted.

Cambridge-based Ironwood Pharmaceuticals inc. is in a new drug-discovery collaboration with Redwood City, Calif.-based Protagonist Therapeutics inc., which will use its proprietary technology for developing peptide drugs against biological targets picked by Ironwood.

© Copyright 2011 Globe Newspaper Company.

Canadian medical bodies should assess as quickly as possible whether there is merit to Paolo Zamboni’s theory of multiple sclerosis: that vein blockages play a key role, and that a simple treatment that opens the veins alleviates many of the symptoms.

Putting Dr. Zamboni’s theory to the test may, as critics say, give false hope to patients who suffer greatly from a neurological disease that may disturb their ability to hear, see, remember and move. Then again, the tests may prove promising. the real question is whether there’s a credible case for pressing ahead with more study.

It is not as if Dr. Zamboni, of Italy, dismisses the idea that multiple sclerosis is an autoimmune disorder. far from it. He says that vein blockages draining blood from the head back to the heart may also contribute to the disorder. his preliminary work suggests it does.

St. Joseph’s Healthcare Hamilton, a leading Ontario hospital affiliated with McMaster University, believes Dr. Zamboni’s theory is worth testing. the hospital is not offering to unblock people’s veins. it will use magnetic resonance imaging and ultrasound to determine whether people with MS are more likely to have vein blockages than those who don’t have MS. the University of Buffalo has begun a similar study, and preliminary results confirmed Dr. Zamboni’s suspicions; 56 per cent of the MS patients had the blockages, more than twice the rate as in those without MS. But studies from Sweden and Germany have reported no differences in the rate of vein blockages.

MS wouldn’t be the first disease to undergo a rethinking. In 2005 Barry Marshall and J. Robin Warren won the Nobel Prize in medicine for challenging “prevailing dogmas” (as the Nobel committee put it) on peptic ulcer disease. (Dr. Marshall drank a glass of bacteria and infected himself to prove the skeptics wrong.) “Revolutionary ideas don’t sit comfortably with the medical community,” says Ian Rodger, the vice-president of research at St. Joseph’s. Skepticism is justified, but it shouldn’t shut down exploration.

Saskatchewan Premier Brad Wall gave life to a national debate when he announced that his province would fund clinical studies of the treatment. this week, Manitoba’s Health Minister, Theresa Oswald, called on her provincial counterparts to support multi-site trials. Quebec Health Minister Yves Bolduc expressed interest on Wednesday. They are right to be having this discussion. Saskatchewan has the country’s highest rate of MS, and with up to 75,000 patients, Canada has among the highest rates in the world. There’s an obligation not to sit on our hands.

Canada should examine its options for testing Dr. Zamboni’s hypotheses, and answer definitively whether the hope is false or real.