Researchers found that an experimental drug safely reduced Alzheimer’s pathology and improved the cognition in elderly squirrel monkeys. The team now plans to test the treatment in a Phase 1 trial in humans.
Scientists in the field of Alzheimer’s have struggled to carry promising findings in mice studies into human trials, but primate researchers believe that animals like monkeys — with brains and bodies that much more closely resemble humans — could be the missing link. Before investing the vast resources required for clinical trials, they hope that testing experimental Alzheimer’s treatments in non-human primates could improve the dismal track record of Alzheimer’s trials.
Taking this approach, a group of scientists have recently found that an immunotherapy treatment known as CpG oligodeoxynucleotides (CpG ODN) boosted aged squirrel monkeys’ immune systems and safely cleared Alzheimer’s pathology in their brains. The findings build on the team’s past research in mouse models, and they are now planning to test CpG ODN’s effects in patients.
Dr. Thomas Wisniewski, professor of neurology, pathology and psychiatry at New York University Grossman School of Medicine who is the co-senior author of study, said CpG ODN reduced the accumulation of beta-amyloid proteins, a telltale sign of Alzheimer’s, and improved cognitive functions in elderly squirrel monkeys.
“It was clear that stimulation of the innate immune system is successful in leading to behavioral benefits, reductions of beta-amyloid burden without any evidence of toxicity,” Wisniewski told Being Patient of CpG ODN’s effects on the squirrel monkeys.
He added that there has been “certainly no evidence of things like hemorrhage or excessive inflammation — the sorts of complications that are plaguing antibody clinical trials,” referring to the amyloid-related imaging abnormalities (ARIA) — a known side effect reported in human clinical trials of immunotherapies including Aduhelm, the drug recently approved by the Food and Drug Administration. Complications of ARIAs include brain swelling and bleeding, and inflammation related to amyloid in the brain’s blood vessels.
Like humans, squirrel monkeys naturally develop amyloid pathology — like beta-amyloid plaques within the brain’s gray matter — as they age, whereas mice brains don’t naturally produce beta-amyloid; mice are genetically engineered in the lab to produce high levels of these proteins. Squirrel monkeys’ amyloid pathology is actually largely found in the brain’s blood vessels, rather than in the gray matter of the brain. But this condition, known as cerebral amyloid angiopathy, occurs in nearly all human patients with Alzheimer’s, according to Wisniewski and colleagues. Given that ARIAs are linked with the presence and clearance of cerebral amyloid angiopathy, aged squirrel monkeys are thereby ideal models for testing CpG ODN’s safety and effects, the team wrote.
For the study, published in Brain, eight elderly squirrel monkeys received monthly infusions of CpG ODN and a control group of seven age-matched monkeys were given saline solutions over a two-year period. Wisniewski and colleagues observed the monkeys’ behaviors, measured their cognitive functions, and analyzed samples of their brain tissue and blood.
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The team found that the drug triggered beneficial immune responses in the treated monkeys, without leading to excessive and sustained inflammation. These monkeys’ learning skills and ability to remember their surroundings were far better than those in the control group, and similar to younger monkeys. Additionally, the treatment group had lower levels of amyloid pathology compared to the control group.
Wisniewski said CpG ODN can enhance the ability of the microglia and macrophages, cells in the immune system, to clear harmful proteins in the brain like the build-up of beta-amyloid. But stimulating these cells is a double-edged sword; overstimulation can lead to harmful levels of inflammation — a stumbling block of past attempts to target the immune system, he explained. Monthly injections of CpG ODN offer the chance for microglia and macrophages to rest, avoiding excessive inflammation, and the dysfunction and death of neurons.
“We were spacing out the stimulation so macrophages and microglia had the opportunity to return to baseline. It was like a pulsed stimulation. You’re enhancing their ability, but then you’re allowing them to go back to normal more or less,” he said of macrophage and microglia activity, “and then you repeat this in multiple cycles. It’s like giving pulses of chemotherapy with a chance for recovery in between.”
While animal testing, including experiments on monkeys, remains controversial, primate researchers say that the genetics, physiology, anatomy and cognition of non-human primates are much more comparable to humans than rodents: Non-human primates could offer insights not only into aging and disease, but also shed light on the potential of experimental therapies for Alzheimer’s like CpG ODN.
With positive results from studying elderly squirrel monkeys, the team is planning to launch a Phase 1 clinical trial of CpG ODN by the end of this year, involving 30 participants with early-stage Alzheimer’s.