Novel "Prodrug" JM6 Alleviates Symptoms in Huntington's and Alzheimer's Mice

A "prodrug" called JM6 has been found to protect against the neurodegenerative effects of both Huntington's and Alzheimer's disease in mice.

It has been reported that a recent study has discovered a “prodrug” called JM6 which is a novel slow-release compound that has been found to protect against the neurodegenerative effects of both Huntington's and Alzheimer's disease in mice.

The compound works through the kynurenine pathway, a major route of amino acid tryptophan breakdown. According to Muchowski, scientists have suspected the pathway to play a role in neurodegeneration since the late 1970s.

Metabolites of the pathway can lead to excessive stimulation of neurons, causing damage and even death of the cells.

The most surprising part of this find, however, is that these benefits are delivered by JM6 even though the compound cannot act directly on the brain: it does not cross the blood-brain barrier.

"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. As this is not the case, this study may open the door to new strategies for the treatment of brain diseases more broadly, stated Muchowski.

Muchowski's team began with a compound designed initially to target an enzyme called kynurenine 3-monooxygenase or KMO. When KMO is repressed, it forces the kynurenine pathway in a direction that amplifies production of a neuroprotective compound known as kynurenic acid (KYNA). KYNA levels are well-known to decline in Huntington's and Alzheimer's brains.

But unfortunately, the researchers discovered that the starting compound (Ro 61-8048) was unsound and degraded quickly.

Luckily for Muchowski, his recently retired father Joseph Muchowski is a synthetic chemist with experience in drug development. Muchowski enlisted his father to help generate a slow-release prodrug version of the KMO inhibitor, which they call JM6.

Initially, the researchers treated mice with Huntington's disease with JM6. Chronic delivery of JM6 inhibited KMO in the animals' blood, which increased kynurenic acid levels and reduced extracellular levels of the chemical messenger glutamate in the brain.

According to Muchowski, these mice would normally have died by the time they were fifteen weeks old, but those treated with JM6 lived about 40% longer than they otherwise would have. He reported that 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. In other words, "JM6 helped the animals remember," Muchowski said.

The untreated Alzheimer's mice often become uninhibited, and will run out of the safety of the dark and into open spaces, which is a risky habit in nature because predators could easily choose such a mouse as their next meal. But Muchowski stated that "JM6 completely rescued that deficit.”

Muchowski said the preservation of synapses they observed is especially important, as memory loss in Alzheimer's patients correlates more directly with the loss of synapses than with the loss of neurons.

Muchowski reported that he and his researchers plan to test the drug's use in humans through clinical trials, but since JM6 is a new compound, there must be trials performed first to test the drug’s safety and toxicity.

He anticipates the first trials with Huntington’s disease patients to be underway in about two year's time.

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

This study appears in a special early online publication of Cell.