BOSTON – Although there is still no cure for Alzheimer’s disease, a new drug that may come in pill form is giving hope to millions of dementia patients worldwide. The researchers say the potential Alzheimer’s drug prevents the disease in mice, rats and monkeys during laboratory experiments.
The results are so “promising” that the researchers expect clinical trials to begin in the coming months. This drug can also prevent cognitive breakdown in genetically prone people who do not yet have the disease. The study authors say that vulnerable individuals would be able to obtain the medication after a simple blood test.
Aiming at plaque build-up in the brain
A team from the University of California San Diego School of Medicine and Massachusetts General Hospital say the treatment belongs to a family of drugs called GSMs (gamma-secretase modulators). It works by destroying harmful proteins, beta-amyloid (Aβ), which form sticky clusters in the brain and destroy neurons.
“In this study, we pharmacologically characterize a potent GSM that, based on its pre-clinical attributes, appears to match or exceed the potency of any previously tested GSMs,” said co-author Dr. Rudolph Tanzi in a press release. “Future clinical trials will determine whether this promising GSM is safe in humans and can be used to effectively treat or prevent Alzheimer’s disease.”
The researchers are awaiting approval from the U.S. Food and Drug Administration for the start of phase 1 studies.
“We hope to start this year. It would be a typical single and multiple ascending dose in healthy individuals. If we move from phase 1, phase 2A would be in Alzheimer’s patients and would include analysis of biomarkers to reduce beta-amyloid in the brain, ”adds Dr. Tanzi in a statement to SWNS.
“Ultimately, we expect our gamma secretase modulators to be safe and effective enough for use in preventing Alzheimer’s – similar to the way we use statins to prevent heart disease,” continues the Massachusetts General Hospital researcher and professor of neurology at Harvard. “Just as we have to reduce cholesterol levels early in life, for decades, to avoid heart disease later in life, we will need to reduce beta-amyloid levels in the brain in early life, for decades to reduce the risk of Alzheimer’s . This means that the medicine we use to do this must be safe, cheap and easy to administer – for example, a small molecule pill ”.
What causes normal proteins to trigger Alzheimer’s?
Beta-amyloid is a normal protein. Everyone has. In patients with Alzheimer’s, however, the process of releasing these proteins goes wrong. Other enzymes, including gamma-secretase, small fragments of fuel or Aβ peptides. The body cannot recognize them, so it cannot get rid of them.
In healthy gray matter, enzymes such as alpha secretase cut Aβ in half. The two bits (of equal size) are cleared and everything is fine. Gamma-secretase, on the other hand, cuts it in unusual places. The toxic particles accumulate, triggering the neurological disorder and its devastating symptoms of memory loss and confusion. In addition, the production of these toxins is greater in patients with mutations that predispose them to early-onset Alzheimer’s. Some proteins, such as Aβ42, are particularly prone to building plaques.
“If we ever want to prevent Alzheimer’s by detecting beta-amyloid levels in the brain in middle age with a blood test, we will probably need a safe and inexpensive pill to do this – similar to the way we use statins to prevent heart disease today ”, Dr. Tanzi explains to SWNS.
“We believe that there could be tens of millions of people in the US now that they would need to start controlling the accumulation of beta-amyloid in the brain. We hope that our secretase gamma modulator will someday be able to do just that. “
GSMs can finally clean up damaged brains
Several previous attempts to block gamma-secretase have failed. Scientists consider the drugs unsafe because the body needs gamma-secretase to cleave other proteins. GSMs, however, change activity only slightly, so that the body produces less Aβ peptides. This allows the chemical to perform the rest of its functions.
“GSMs, therefore, offer the ability to mitigate the mechanism-based toxicities associated with γ-secretase inhibitors,” said UCSD co-author Steven Wagner.
Repeated low doses of GSM completely eliminated Aβ42 in mice and rats without any toxic side effects. The drug was also safe and effective in monkeys, reducing Aβ42 levels by up to 70 percent. Other tests on mice genetically engineered to carry mutations that cause Alzheimer’s disease were also encouraging.
The researchers treated the animals before or shortly after they started to form amyloid plaques. In both cases, the compound reduced them and also decreased brain inflammation. GSMs also attacked microglia, inflammatory cells that can contribute to the disease.
“This suggests that the drug can be used prophylactically to prevent Alzheimer’s in patients with genetic mutations that increase susceptibility or where plaques have been detected by brain scans,” adds Prof. Wagner. “Our planned phase I study will be carried out on healthy normal individuals. Approximately 100 people are expected to be registered. “
The study was published in Journal of Experimental Medicine.
SWNS writer Mark Waghorn contributed to this report.