After a decade, scientist's quest to make a better Alzheimer's drug shows progress - Palm Beach Post (blog)

There's no cure for Alzheimer's, and the few drugs available don't work well. /PB Post

Namenda.

You may not have heard of Namenda. People caring for Alzheimer’s patients have.

It’s one of the only drugs available to treat people with advanced dementia.

But it’s no cure.

Sanford-Burnham’s Dr. Stuart Lipton readily acknowledges that, even though he helped developed the drug for FDA approval, back in his Harvard days. It was designed to protect synapses, the linkages between brain cells, from the small toxic plaque clumps found in the brains of people who have Alzheimer’s. He’s spent the past decade studying how to improve the drug.

The numbers of people living with Alzheimer’s is now estimated at over 5 million in the United States, and projected to grow to 13 million by mid-century. Palm Beach County has an estimated 46,000 Alzheimer’s patients.

The need for better drugs is immense, said Lipton, who is both a researcher and a physician.

At LaJolla’s Sanford-Burnham Medical Research Institute now, Lipton spends his days contemplating how one bit of a molecule attracts or repels another bit. Disease cures depend on such esoterica.

He explains: Namenda, whose generic name is Memantine, isn’t working as well as it should based on its molecular shape, Lipton said. He blames the north-north problem.

Think magnets.

Try to push the same ends of two bar magnets together, and they don’t attract. They repel. That’s what happens when memantine reaches a damaged neuron, he said. It has a positive charge. So does the damaged neuron. The drug winds up being repelled by its intended target, Lipton said.

And so he’s been searching for another piece of a molecule to allow opposites to attract, to allow the drug to hit the target on the neuron, every time.

In a paper published in the Proceedings of the National Academy of Sciences on June 16, he declared victory.

After 37 different tries, he said his team had created a new drug molecule that has shown itself totally able to halt plaque-driven synapse death. It worked in dishes in the lab. It worked in two types of rodents. Now he’s ready to try it in humans.



He’s hopeful that halting synapse death will preserve aging neurons’ ability to form new connections, to learn, remember and survive. Further, it’s made from two already-approved drugs, memantine and the it’s more likely to be safe and well-tolerated by patients, Lipton believes.

Dr. Stuart Lipton

“What I find encouraging is one, it takes two FDA approved drugs and combines them, increasing the odds they will be well-tolerated,” Lipton said. “Second, this is the first drug that brings the synapses all the way back to normal.”

He has called his new molecule NitroMemantine. The name reflects what the drug actually is – a fragment of the long-used cardiac drug, nitroglycerine, glued onto his memantine HCl molecule.

Together, they showed the ability to stop the of plaque on brain cells called astrocytes. Lipton and his team described that cascade in exhaustive detail in their PNAS paper:

When an astrocyte brain cell comes in contact with plaque, the plaque triggers the cell to release a toxically intense burst of an otherwise useful neurotransmitter called glutamate.

Overwhelmed with glutamate, brain cells’ branches recoil, and synapses are broken. The ability to remember, reason and think shrinks along with the cells’ synapses.

NitroMemantine blocks the glutamate burst from damaging the cells.

Scripps Florida neuroscientist Roy Smith called the research on the glutamate cascade “most elegant.” But he added that even the most positive research on memantine has shown it delays, but does not stop the disease’s progress. He was hesitant to agree that a major breakthrough has been made.

Max Planck Florida Scientific Director Ryohei Yasuda has found a different protein amplified by the brain plaque of Alzhiemer’s, which he calls centaurin. He’s now looking for a compound to block the plaque from acting on centaurin. Will that succeed in preserving brain cells? It’s unclear. He’s likewise uncertain whether centaurin has a role in the glutamate burst that Lipton’s paper described. More research is needed.

“Maybe it’s not so easy to get an actual cure,” Yasuda said. “But all of us are working very hard.”

Lipton said moving NitroMemantine into human trials will require a larger pharmaceutical company partner, because of the cost. He’s in talks now, he said.

Many other promising Alzheimer’s drugs have emerged, only to have their development halted because they didn’t work or they proved to have dangerous side effects in clinical trials. Eli Lilly recently halted trials of a drug known only as LY2886721 because of liver toxicity. Yasuda noted that nitroglycerin is used to lower blood pressure.

“It’s not easy to predict what the drug will do,” Yasuda said. “I think there is potential. I think we just have to wait until there are human trials.”

Lipton says there’s evidence that blocking the effect of the glutamate burst can stop other toxic processes seen in Alzheimer’s brains, such as the development of tangles of fibers. And he thinks that preserving synapses will keep neurons from dying in Alzheimer’s patients. The research continues.

“This is about a decade of work,” Lipton said. “These things take a long time. Understanding the basic mechanism is critical in understanding what makes a drug work.”

This entry was posted on Wednesday, June 26th, 2013 at 5:53 pm and is filed under Alzheimer's, Article, Drugs, Scientific research. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

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