Scientists have developed a new drug that modulates a key enzyme responsible for forming the amyloid plaques linked to the onset of Alzheimer’s disease.
(CN) — Researchers unveiled new evidence that a novel Alzheimer’s drug could prove effective in treating patients with early signs of the disease – though less so in its later stages.
A team from the University of California San Diego School of Medicine and Massachusetts General Hospital published a study Tuesday in the Journal of Experimental Medicine demonstrating the drug’s effectiveness in monkeys, rodents and birds, which could pave the way to human trials.
Alzheimer’s disease is thought to be caused by the buildup in the brain of amyloid plaques made from protein fragments called peptides, particularly one called Aβ42. Peptides form when enzymes break apart certain proteins in the brain, called amyloid precursor proteins, into their constituent amino acids.
When these Aβ42 peptides bind together, they form amyloid plaques which accumulate and can eventually lead to Alzheimer’s disease. Some individuals are genetically predisposed to developing higher levels of these peptides, putting them at increased risk of early-onset Alzheimer’s.
“In this report, we detail the preclinical pharmacology of a potent and efficacious pyridazine-based GSM referred to as compound 2,” the authors write in their study. “The robust in vivo potencies exhibited by compound 2 across species, combined with the preliminarily acceptable safety profile based on both the efficacy and the DRF toxicology studies, strongly suggest the possibility of this compound being capable of providing a wide therapeutic index in humans.”
Previous attempts at treating the disease involved drugs that completely inhibit the Aβ42 peptide. Unfortunately, those efforts didn’t pan out because the peptides responsible for forming the amyloid plaques that cause Alzheimer’s are also required for necessary brain function.
This time researchers tried something new — by employing a class of drug known as y-secretase modulators (GSMs), they were able to control the formation of these sometimes-harmful-sometimes-useful peptides rather than cutting them out entirely. The drug acts on the enzyme that cleaves these proteins, allowing them to produce enough Aβ42 for healthy brain function, but not so much that harmful amyloid plaques develop.
“GSMs therefore offer the ability to mitigate mechanism-based toxicities associated with γ-secretase inhibitors,” said Steven Wagner, a professor in the Department of Neurosciences at UC San Diego School of Medicine, in a related statement.
Researchers believe the new drug will be most effective in patients with early signs of Alzheimer’s and in those who are genetically predisposed to getting the disease. They warn that it’s less likely to benefit individuals who are already symptomatic because the drug helps prevent amyloid plaque from forming but doesn’t reverse damage that has already been done.
By repeatedly administering low doses of the new drug, the team was able to completely curtail Aβ42 production in rats and mice without causing harmful side effects. It also reduced Aβ42 levels in macaques by up to 70%. The test animals who received the drug in the early stages of the disease displayed reduced plaque formation and lower levels of plaque-induced inflammation, another significant contributor to the onset of Alzheimer’s.
“Acute, subchronic, and chronic efficacy studies demonstrated significant lowering of Aβ42 levels in plasma, cerebrospinal fluid, and brain extracts of rats and mice at doses ∼5–10-fold lower than those required for previously developed GSMs,” said the authors in their study.
The real test will come when researchers begin human trials, which they hope to move onto in the near future. The major benefits of the new drug would be as a preventative treatment for individuals already genetically predisposed to developing Alzheimer’s, and for patients in the very early stages of the disease, rather than existing sufferers as it’s not able to reverse existing damage.
“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,” adds co-author Dr. Rudolph Tanzi, professor of neurology at Harvard and Massachusetts General Hospital, in a related statement. “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.”