‘Promising’ Alzheimer’s pill could stop disease in its tracks, human trials to start soon

BOSTON — Although there’s no cure for Alzheimer’s disease yet, a new drug that could come in pill form is giving hope to millions of dementia patients around the world. Researchers say the potential Alzheimer’s drug prevents the disease in mice, rats, and monkeys during lab experiments.

The results are so “promising,” researchers expect clinical trials to begin in the next few months. Such a drug may also ward off the cognitive breakdown in genetically prone people who don’t have the condition yet. Study authors say vulnerable individuals would be able to get the medication after a simple blood test.

Targeting plaque buildups 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 rogue proteins, beta-amyloid (Aβ), that form sticky clumps in the brain and destroy neurons.

Amyloid plaques
Compared with a control (left), treatment with the novel GSM (right) reduces the number of amyloid plaques (green) and proinflammatory cells called microglia (magenta) in the brains of mice carrying mutations linked to early-onset Alzheimer’s disease.

“In this study, we have pharmacologically characterized a potent GSM that, based on its preclinical attributes, appears to equal or exceed the potency of any previously tested GSMs,” says lead co-author Dr. Rudolph Tanzi in a media release. “Future clinical trials will determine whether this promising GSM is safe in humans and could be used to effectively treat or prevent Alzheimer’s disease.”

The researchers are awaiting approval from the U.S. Food and Drug Administration for phase 1 studies to begin.

“We hope to get started this year. It would be a typical single and multiple ascending dose in healthy individuals. If we are get through phase 1, phase 2A would be in Alzheimer’s patients and include looking at biomarkers for reducing beta-amyloid in the brain,” Dr. Tanzi adds in a statement to SWNS.

“Ultimately, we hope our gamma secretase modulators will be sufficiently safe and effective for use in preventing Alzheimer’s – similar to how we use statins to prevent heart disease,” the Massachusetts General Hospital researcher and Professor of Neurology at Harvard continues. “Just like we have to lower cholesterol levels early in life, for decades, to avoid heart disease later in life, we will need to lower brain beta-amyloid levels early in life, for decades to reduce risk for Alzheimer’s. This means the drug we use to do that must be safe, inexpensive and easy to administer – for example, a small molecule pill.”

What makes normal proteins trigger Alzheimer’s?

Beta-amyloid is a normal protein. Everyone has it. In Alzheimer’s patients however, the process for flushing these proteins out goes awry. Other enzymes, including gamma-secretase, fuel small fragments, or Aβ peptides. The body can’t recognize these so it’s unable to get rid of them.

In healthy grey matter, enzymes like alpha secretase snip Aβ in the middle. The two bits (of equal size) are cleared and all is well. 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. Moreover, production of these toxins is higher in patients with mutations that pre-dispose them to early-onset Alzheimer’s. Some proteins, such as Aβ42, are particularly likely to build plaques.

“If we are someday going to prevent Alzheimer’s by detecting brain beta-amyloid levels at middle age with a blood test, we will likely need a safe and inexpensive pill to do so – similar to how we use statins to prevent heart disease today,” Dr. Tanzi explains to SWNS.

“We believe there could be tens of millions people in the USA right now that would would need to start controlling beta-amyloid accumulation in the brain. We hope our gamma secretase modulator will someday be able to do just that.”

GSMs may finally clean up damaged brains

Several previous attempts to block gamma-secretase have failed. Scientists consider the drugs unsafe as the body needs gamma-secretase to cleave other proteins. GSMs however, only slightly alter activity so the body produces fewer Aβ peptides. This enables the chemical to perform the rest of its roles.

“GSMs therefore offer the ability to mitigate mechanism-based toxicities associated with γ-secretase inhibitors,” lead co-author Professor Steven Wagner from UCSD says.

Repeated low doses of the GSM completely eliminated Aβ42 in mice and rats without any toxic side-effects. The drug was also safe and effective in macaques, slashing levels of Aβ42 by up to 70 percent. Further tests on mice genetically engineered to carry mutations that cause Alzheimer’s were equally encouraging.

Researchers treated the animals before or shortly after they began to form amyloid plaques. In both cases, the compound reduced them and lessened brain inflammation too. GSMs also attacked microglia, inflammatory cells which may contribute to the disease.

“This suggests the drug could be used prophylactically to prevent Alzheimer’s in patients with genetic mutations that increase susceptibility or where plaques have been detected by brain scans,” Prof. Wagner adds. “Our planned phase I trial will be carried out in healthy normal subjects. Approximately 100 people are expected to be enrolled.”

The study was published in the Journal of Experimental Medicine.

SWNS writer Mark Waghorn contributed to this report.

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