Stuart Lipton offers a new possible reason why all the Alzheimer's drugs have failed
There are a few commonly trotted out reasons for why virtually every Alzheimer’s drug of the last two decades has failed: Maybe the trials didn’t start early enough in the course of disease, or maybe they didn’t go after the right group of patients?
As companies have started earlier and on more select groups of patients, another conclusion has grown increasingly popular: Maybe they’ve all gone after the wrong target. Maybe clearing the misfolded plaques that buildup in patients’ brains, as these therapies have, just wipes away one symptom of the disease but not the root cause.
Stuart Lipton, though, has an alternative explanation. A leading dementia expert who helped develop the the last FDA-approved Alzheimer’s drug, he is publishing new research this week showing that the antibodies companies developed might be having an unintended side effect that undercuts any benefit they offer.
Amyloid-clearing antibodies, he wrote in a paper for the Proceeding of the National Academy of Science, might be setting off dangerous inflammation that, in a cruel bit of irony, hasten neurological decline. Lipton called the result paradoxical.
“We realized that it’s possible these human trials, many of which have failed, might be in part failing because they’re paradoxically inducing more inflammation in the brain,” he told Endpoints News, “even though they’re getting rid of the protein, which may be a good thing.”
The research began when a postdoc at Lipton’s Scripps Institute lab, Dorit Trudler, attempted to make the innate immune cell of the brain, an octopus-looking goop called the microglia, in the lab. It’s a difficult task because microglia don’t come from the same lineage of stem cells in the bone marrow that the rest of the immune system, B cells and T cells and macrophages, do.
Instead, it comes from the yolk sac that bathes embryos in early development, migrating from the sac to the brain. By giving human-derived stem cells a series of molecular signals, Trudler turned them into a cluster that resembled a yolk sac and, from it, developed cells that, based on the mRNA they express, were indistinguishable from microglia removed from humans.
“They match as closely as possible,” Lipton said.
Because human microglia are difficult to produce, drug researchers have historically used mouse models to see how the immune cells respond to drugs. Lipton and Trudler, though, were able to simulate how human microglia respond in the brain.
They found that if you exposed these microglia to either alpha synuclein, the hallmark misfolded protein in Parkinson’s, the microglia sent off inflammatory signals. And if you added amyloid-beta, the inflammation worsened.
Finally, they managed to obtain antibodies that companies had developed to bind to and clear those misfolded proteins. (Lipton declined to say which antibody it was, except that, despite his best efforts to convince the drugmaker, it wasn’t Biogen’s aducanumab, the controversial candidate now before the FDA.)
To their surprise, the antibodies successfully binded to the misfolded protein but that didn’t help inflammation. “Rather than make things better, it actually made things worse,” Lipton said.
By looking at humanized mice that had both human and mice microglia, Lipton’s team found that the pro-inflammatory response was unique to the human cells, meaning drugmakers wouldn’t have seen it in the translational studies. They’re still not sure why it’s causing inflammation, but they showed the effect with multiple different antibodies that target multiple different proteins and they’ve nailed down the pathway, NLRP3, that’s involved.
Still, Lipton said, they don’t necessarily have to figure out the exact mechanism. He says you could imagine giving these amyloid-clearing drugs in combination with a drug that blocks inflammation, allowing doctors to clear out misfolded proteins without dangerously turning up the heat.
In fact, it’s what his lab is working on right now.
“We’re hopeful that we can maybe develop a drug in the near future that can offset,” Lipton said.