Drug creation for Alzheimer’s disease poses a dilemma: Because the enzyme behind the condition is crucial for several body processes, tampering with it is risky. But scientists have now discovered a way to safely control the enzyme, offering hope that the disease will soon have its first dedicated medication.
Alzheimer’s disease is caused by the accumulation of amyloid plaques. An enzyme called γ-secretase produces Aβ peptides which gather in the brain and form deposits of these plaques in between neurons, ultimately reducing cell activity. But, because γ-secretase metabolizes a significant number of other membranes in the brain, inhibiting it is out of the question. Attempts to do so have proven unsafe in humans.
Addressing this problem, researchers published a paper Tuesday in The Journal of Experimental Medicine, introducing a new party to the equation — a molecule that regulates the plaque-forming peptides without reducing non-negotiable enzyme levels. Their new drug is what is known as a γ-secretase modulator, or GSM, and it effectively slowed disease progression in mice, rats and macaques by 70%.
“We can’t inhibit these peptides because they’re important, but we can cleave them to avoid plaque creation,” Steven L. Wagner, a professor of Neuroscience at University of California, San Diego, and the paper's lead author told The Academic Times.
The researcher is especially optimistic because this is the first time that a drug, which doesn’t inhibit enzyme levels, has shown any sort of promise in treating a neurodegenerative disease. Currently, there is no neurodegenerative disease with a cure or medication aimed specifically at treating the disease rather than its symptoms.
Heavily funded by the National Institutes of Health, Wagner says the new drug will enter phase 1 clinical trials in humans this year. It will be a pill that patients take orally once a day, comparable to aspirin.
The γ-secretase modulator tackles the specific feature of the peptides that leads to amyloid deposits — their size.
“The length of the fragment is important,” Wagner said. “Long is bad in neurodegeneration; the longer they are, the more insoluble they are.”
Peptides are a chain of amino acids that vary in size. Cleaving a fragment of a peptide means cutting it at a specific location on the chain, and the team’s molecule does so in such a way that harmful long peptides are no longer produced. This prevents peptide accumulation and therefore amyloid plaque deposits in the brain, slowing the effects of Alzheimer’s.
“We call it allosteric modulation," Wagner said. “We think that it hits it at an allosteric site that just causes it to cleave the Aβ peptides at a different position.
Wagner has been working on Alzheimer’s disease treatment ideas for the last 15 years, and noted that during this time, he and his team have been testing a multitude of molecules that can modulate the enzyme and working to perfect the drug.
Because of the delicate nature of the enzymes being targeted, they had to ensure that adverse side effects are extremely unlikely to occur, as opposed to what happened when scientists tried inhibiting the enzyme altogether.
“The thought was that if you block the enzyme, you could basically prevent the peptide from forming, and it wouldn't accumulate into plaques, but that approach turned out to be, not very feasible,” Wagner said, pointing out the drastic side effects that occurred, including cognitive worsening.
Wagner emphasized that his new approach has, so far, passed every level of extensive safety testing that the team has put it through. He believes it can safely slow the formation of amyloid plaques in the brain, regardless of age or disease severity.
Further, he says that this drug is workable for victims of early-onset Alzheimer’s, explaining that with the tools available to scientists now, like positron emission tomography, PET, imaging and genetic testing, it’s possible to know which individuals are predisposed to amyloid plaques.
“There are close to 300 different mutations in these these three genes, which basically cause individuals to develop Alzheimer's disease when they're at a very young age,” he said.
Those who are genetically predisposed to developing Alzheimer’s can start accumulating amyloid deposits in their brain early in life. Citing work published by Randy Bateman, a professor of neurology at Washington University and a strong endorser of the new drug, Wagner says that individuals with specific genetic mutations synthesize the dangerous long-form peptides that lead to Alzheimer’s.
Even though he attributes his team’s finding of the particular special molecule to chance, Wagner relayed that the team worked hard to take advantage of it and that it is a large step forward that he intends to stick with.
“At least we've got something to test," he said, “That's the exciting thing about it. And if we fail here, we’re not going to quit. We’ve got backup molecules.”
The paper, “Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention,” was published March 2 in The Journal of Experimental Medicine. It was authored by Kevin D. Rynearson, Olga Prikhodko, Yuhuan Xie, Phuong Nguyen, Mariko Sawa, Ann Becker, Brian Spencer, Jazmin Florio, Michael Mante, Bahar Salehi, Carlos Arias, Douglas Galasko, Robert A. Rissman, William C. Mobley and Steven L. Wagner, University of California, San Diego; Moorthi Ponnusamy and Gopal Thinakaran, University of South Florida; Martin Zhang and Rudolph E. Tanzi, Massachussetts General Hospital; Brenda Hug and Brian P. Head, Veterans Administration San Diego Healthcare System; Graham Johnson, NuPharmAdvise; Jiunn H. Lin, Biopharm Consulting Partners; Steven K. Duddy, Integrated Nonclinical Development Solutions. The lead author was Steven L. Wagner.