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A New Hope: Oral Slow-Release Compound Protects Mice From Neurodegenerative Damage

BrightFocus-Funded Researchers Discover New Drug that Helps Both Alzheimer’s and Huntington’s Diseases

June 6, 2011

A breakthrough discovery that could bring hope to millions with Alzheimer's and Huntington's diseases was published on June 3 in a special early online edition of the preeminent journal, Cell.

A new slow-release oral drug given to mice engineered to show features of Alzheimer's disease prevents spatial memory deficits, anxiety-related behavior and the loss of “synapses”—the nerve communication centers critical for brain cell survival, signaling, and memory. The study was supported by a BrightFocus Foundation research fellowship grant to Dr. Daniel Zwilling.

The new drug, called JM6, ultimately results in changes to the amount of break down products of an amino acid, called tryptophan. Problems with tryptophan processing have been linked to many serious diseases. More specifically, JM6 is converted by the gut to a form that, through a chain of reactions, increases the brain levels of a protective chemical called kynurenic acid. The effect of this new drug is exciting because people with Huntington's and Alzheimer's diseases have lower than normal amounts of kynurenic acid in their brains.

There is hope that since JM6 protects mice from neurodegenerative damage, it could be used as a treatment for humans. Drs. Muchowski, Zwilling and collaborators are preparing for Phase I clinical trials. They may first test the safety and toxicity of JM6 in people with Huntington's disease as early as 2013.

Original publication is in the journal Cell: http://www.cell.com/fulltext/S0092-8674(11)00581-2

For more information, see the press release below.

 A study in a special early online publication of Cell, a Cell Press publication, reveals a promising new slow-release compound that protects mice against the neurodegenerative effects of both Huntington's and Alzheimer's disease. The 'prodrug' known only as JM6 works through a pathway involved in the breakdown of the amino acid tryptophan.

Surprisingly, JM6 delivers those benefits even though it doesn't cross the blood-brain barrier and therefore cannot act directly on the brain.

"Most would have assumed that the drug would have to enter the brain to have an effect," said Paul Muchowski of the University of California, San Francisco. He says the new study may therefore pave the way to new strategies for the treatment of brain diseases more broadly.

The kynurenine pathway is a major route of tryptophan breakdown. Scientists had suspected the pathway to play a role in neurodegeneration since the late 1970s, Muchowski said. Metabolites of the pathway can lead to excessive stimulation of neurons, causing damage and even death of the cells.

They first treated mice with Huntington's disease with JM6 that normally would have died by the time they were 15 weeks old, lived about 40 percent longer than they otherwise would have, Muchowski said. Their motor coordination improved and they were protected against the loss of the synapses that serve as critical junctions in the neural circuitry.

In a transgenic mouse model of Alzheimer's disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and the loss of synapses. "JM6 helped the animals remember," Muchowski said.

Alzheimer's mice also become uninhibited and will run right out of the safety of the dark and into open spaces, a risky habit in the real world where predators lurk. "JM6 completely rescued that deficit."

Muchowski says the preservation of synapses they observed is especially key. That's because it's known that memory loss in Alzheimer's correlates more closely with the loss of synapses than with the loss of neurons.

Muchowski said they do plan to test the drug's use in humans through clinical trials. Since JM6 is a new compound, they will have to start with trials designed to test the safety and toxicity of the drug. He expects the first trials could be underway in about two year's time in patients with Huntington's disease.

"One way or another, we will move forward," he said.

Adapted from Cell Press

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