Alzheimer’s disease and frontotemporal dementia are among the most crippling disorders, emerging as a result of the accumulation of misfolded proteins within the brain.
The latest wave of Alzheimer’s therapeutics has focused on combating the buildup of the amyloid beta protein using engineered antibodies. However, the outcomes have been far from satisfactory, with a host of adverse effects, and the use of these engineered antibodies often comes with a hefty price tag.
Researchers at Washington University in St. Louis are blazing a new trail. They are aiming to engineer vaccines that can harness a person’s own immune system to target and eliminate the accumulations of amyloid beta and tau proteins.
Thanks to a $2.9 million grant from the National Institute on Aging, which is part of the National Institutes of Health (NIH), researchers Jai Rudra, PhD, an associate professor of biomedical engineering at the McKelvey School of Engineering, and Meredith Jackrel, PhD, an associate professor of chemistry in Arts & Sciences, are set to design vaccines. These will generate anti-amyloid beta and anti-tau antibodies, leveraging Rudra’s innovative peptide nanofiber vaccine platform.
A crucial aspect of this project’s success hinges on vaccine designs that can avoid triggering inflammation. In the field of dementia research, countering the chronic inflammation that accompanies aging has long been a persistent hurdle.
Rudra explained that previous trials resorted to potent vaccine adjuvants to prompt the immune system to attack amyloid beta. But this led to adverse reactions in some patients. While adjuvants can compel the immune system to recognize misfolded proteins as “foreign invaders,” the resulting inflammation can sometimes cause more harm than good. Instead, Rudra is turning to the nanofiber platform he developed in prior vaccine investigations.
“Nanofibers possess unique attributes that make them highly appealing for generating antibodies against tau and amyloid beta proteins, and, crucially, they don’t incite inflammation like other adjuvants,” said Rudra.
Jackrel pointed out that recent trials of dementia treatments have faltered in part due to the brain inflammation they induced. This is precisely why they are opting for the nanofiber approach.
“The non-inflammatory nature of these nanofibers represents a sound strategy to overcome that obstacle,” she said.
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The nanofibers function more effectively because they present amyloid beta and tau proteins on their surface in a manner that prompts the immune system to mount a response with minimal inflammation.
Jackrel and Rudra will collaborate with researchers from WashU Medicine to put their vaccines to the test. Tim Miller, MD, PhD, the David Clayson Professor of Neurology, and Kathleen Schoch, PhD, an assistant professor of neurology, will play a key role by testing the vaccines on transgenic mice that develop brain disorders mirroring various forms of dementia.
They plan to evaluate the vaccines both as a preventive measure and as a treatment after symptoms have emerged, although Rudra anticipates that the prophylactic application will prove more efficacious. The challenge of dismantling tau and amyloid clumps once dementia symptoms have manifested is that it may already be too late.
“Breaking up these clumps is going to be extremely difficult,” Rudra noted, adding that it will likely be far easier to try to halt the progression of dementia symptoms in their infancy, potentially as early as middle age, by nipping neuroinflammation in the bud.
This also dovetails with other initiatives at WashU aimed at developing blood tests for the early detection of a variety of neurodegenerangerative diseases. Additionally, projects outside the realm of biomedical engineering are exploring a diverse range of medical and lifestyle interventions, not just relying on the immune system’s heavy artillery.
“Dementia and neurodegeneration are not monolithic; they don’t stem from a single cause,” Jackrel said. “So, a multi-faceted approach is essential.”
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