You can hear the excitement in Kiminobu Sugaya’s voice, and you hope that what he is telling you comes to pass. “This treatment is hopefully a cure,” the neuroscientist says. When it comes to looking for a cure for Alzheimer’s disease, researchers over the years have focused mainly on the unusual buildup of plaques in the brain, the supervillain of dementia. These plaques are made from a protein called amyloid-beta. Remove the amyloid-beta, the hypothesis goes, and you’ll stop or, at the very least, slow down AD and other dementias.
Unfortunately, finding a way to rid the brain of amyloid-beta or hinder its ability to choke the brain’s cells has been a failure. It’s not for lack of trying: For nearly 30 years, researchers have run into countless roadblocks. The best scientists have been able to do is develop drugs that treat the symptoms of AD, not the underlying affliction.
While cancer drugs used in clinical trials have around a 20 percent success rate, drugs to treat dementia have a 99.6 percent failure rate. It’s a harsh reality. But Sugaya, professor and head of neuroscience at the University of Central Florida, believes he might have found an answer in stem cells.
Stem Cells Showed Early Promise
Stem cells are amazing. They can transmogrify into any type of cell in the human body. Back in the early 2000s, Sugaya transplanted brain stem cells into aged rats. Over a period of a few weeks, the cells seemed to become functional neurons. Those new brain cells, he said, improved age-associated memory loss in the animals. Moreover, there were no side effects.
However, when Sugaya transplanted stem cells into AD model mice, no new neurons formed. It seems a surplus of amyloid-beta precursor protein (APP), a substance that produces plaque, stopped the stem cells from becoming brain cells.
Sugaya has since developed a technique using a newly discovered drug called APC-100, which can pass through the blood-brain barrier. Instead of attacking the amyloid-beta protein directly, the treatment targets APP and increases brain stem cells without transplantation. “Amyloid protein isn’t the bad guy,” Sugaya notes, “but APP is. The plaque is just the result.”
The first thing Sugaya and his team did was to treat AD model mice with a drug that reduced the amount of APP in the brain by nearly 50 percent. The scarcity of APP, Sugaya says, creates an environment in which brain stem cells thrive and morph into young, healthy neurons.
In the past, Sugaya transplanted stem cells into the brains of his laboratory animals. Now Sugaya’s drug, APC-100, spurs the creation of stem cells in the brains of the mice, all by itself. “We saw an amazing effect of 600 percent neurogenesis,” he says. The treatment, he maintains, might some day turn out to be a cure for AD.
The Hope for Cognitive Repair
After he treated transgenic mice with the APC-100 drug, Sugaya says, the mice showed significant cognitive improvement within a few weeks. He believes that humans, regardless of their stage of AD, may someday achieve similar results.
SynapCyte, Sugaya’s biotherapeutic company, is a spin-off from the University of Central Florida. It’s been raising capital to complete preclinical studies before filing APC-100 as an investigational new drug (IND) with the FDA. Next, they’ll conduct a Phase l Human Safety clinical trial. Then, says Bob Hering, SynapCyte’s CEO, “with the proper funding in place, we could be through our Phase ll clinical trial within 36 to 41 months.”
It is an uphill battle. Many treatments found to be very effective in AD animal models fall flat in clinical trials using human subjects. Hopefully, SynapCyte’s clinical trials will mimic the results found in mice. With that understanding, Sugaya and Hering believe they are onto something very special, because their approach is totally different from others.
Legions at Work
Sugaya isn’t the only one diligently at work. Around the world, scientists are researching different models and pathways in hopes of finding a cure or better early-detection methods. Some researchers spend their days developing new brain-imaging techniques for spotting AD before symptoms manifest. Others are studying the brain’s molecular structures, trying to pinpoint Alzheimer’s before it irreversibly changes the brain’s wiring. Still other scientists are looking for biomarkers, those biological cookie crumbs researchers hope might lead to an early and proper diagnosis.
In early July 2017, for example, officials at Biogen and the Japanese company Eisai made a startling announcement. They reported the drug BAN2401, an antibody that targets amyloid-beta protein — first thought to be a failure — showed “statistically significant” evidence of slowing the progression of Alzheimer’s. Biogen said patients taking high doses of the medication lost their cognitive abilities more slowly than those taking a placebo. Moreover, the drug, the company reported, cleared away the sticky tangles of amyloid.
Equally astonishing is that the drug was deemed a failure in 2017 after 12 months. After 18 months of retesting, however, the study’s 856 patients “demonstrated a statistically significant slowing of disease progression,” compared to those taking a placebo, the company said.
“The prospect of being able to offer meaningful disease-modifying therapies to individuals suffering from this terrible disease is both exciting and humbling,” says Alfred Sandrock, MD, executive vice president and chief medical officer at Biogen.
More Studies Needed
In recent years, the theory of attacking amyloid protein has been unpopular, since countless treatments focusing on the buildup of plaque have failed at the clinical level. Biogen’s announcement gave new life to that hypothesis. “This is the first late-stage antiamyloid antibody study to successfully achieve statistically significant results at 18 months, further validating the amyloid hypothesis,” Lynn Kramer, MD, chief clinical officer and chief medical officer of the Neurology Business Group at Eisai, said when announcing the results.
BAN2401 is just one in a series of developments in recent years: Scientists at Lancaster University, in the UK, discovered that a drug for type 2 diabetes “significantly reversed memory loss” in mice. It could prove an effective treatment for AD.
Meanwhile, Roberta Diaz Brinton, PhD, a researcher at the University of Arizona, has developed a neurosteroid that causes stem cells in the brain to generate new brain cells. And German researchers have recently discovered that immune cells in the brain, so-called microglia, are to blame for AD. They say when inflammation occurs in the brain, the microglia release bits of protein that glom onto the amyloid-beta protein, spurring the creation of tangles that can kill neurons and ultimately lead to Alzheimer’s.
An Uncertain Future
The scientific journals are crammed with these and other possible solutions and groundbreaking work. There may well come a time when AD is successfully managed, just like any other chronic illness, slowly whittled down by new drug treatments. The goal is to make sure, regardless of the therapy, that Alzheimer’s disease stops being a burden for patients, caregivers, and society as a whole.
“We can help people to live well with the disease,” says neurologist Daniel Potts. “This is nothing to be ashamed of… we try to embrace people with this. Tell them, ‘We’re going to find new talents you have. We’re going to support what you can still do, empower that, and minimize what you can’t do.’ If I can bring some joy that way and some hope to people, then that’s what motivates me.” A cure is still elusive. All we can do is wait and hope.
A version of this article appeared in our partner magazine, Alzheimer’s: New Hope for a Cure, in 2020.
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