PureTech turns 200-year-old discovery into a new approach to Alzheimer's, while clinging to controversial amyloid hypothesis
Before MRIs or CT scans, 18th-century anatomist Paolo Mascagni injected his cadavers with mercury. Ever mobile, the mercury coursed through their veins like blood, illuminating the body’s rivers and canals in a silvery contrast that Mascagni could trace upon dissection.
In ornate, da Vinci-esque diagrams, Mascagni sketched the bulk of the body’s lymphatic system: The complex drainage networks that assure immune cells flow to the right place and fluid never builds up in any one spot. That included detailed drawings of the lymphatic system in the brain — whose existence scientists promptly forgot for the next 200 years.
As Mascagni’s work, written in Latin, fell into obscurity, researchers came to believe the brain was cut off from the rest of the immune system. Now, in the few years since rediscovering the Italian doctor, scientists are beginning to implicate the system in a host of diseases, including intractable neurodegenerative conditions such as Alzheimer’s.
“They’ve been rediscovered and forgotten,” said Joseph Bolen, CSO of PureTech, a biotech that specializes in the lymphatic system. “What’s been really well established in the past now six years is how important these lymphatics actually are.”
Three years ago, PureTech signed a collaboration with Jonathan Kipnis, the University of Washington immunologist who has led the field’s revival. Kipnis’ research showed that as mice age, the brain’s drainage system begins to break down. It’s as if there’s a clog and the body can’t get rid of harmful proteins associated with Alzheimer’s or other molecules that can trigger dangerous inflammation.
In a new Nature paper Wednesday, Kipnis demonstrated that by giving mice the gene for a growth factor, they can stimulate the body to rebuild that drainage system, potentially improving the efficacy of drugs designed to clear the amyloid plaques that build up in an Alzheimer’s patient’s brain. Now controversial, these treatments have failed nearly every major trial, despite decades of industry investment.
“These are great findings in mice by Kipnis and colleagues, who are really experts in this area,” Stuart Lipton, an Alzheimer’s researcher at the Scripps Institute who was not involved in the research, said in an email.
PureTech is now trying to develop the approach into a treatment for Alzheimer’s. It’s still early stage and the company is remaining tight-lipped, but it would involve figuring out how to deliver the growth factor Kipnis used, called VEGFc, into a patient’s brain at the same time they receive a treatment like Biogen’s amyloid-clearing aducanumab.
The FDA is now weighing an approval aducunamab, but the drug failed one of its two major studies and showed no effect in low doses in either trial. If the lymphatic system is restored, said Bolen, it should be able to clear out more amyloid than the antibody could alone.
Not everyone, though, is convinced. As amyloid-clearing drugs have failed repeatedly, longtime critics of the amyloid hypothesis have become more vocal. Although amyloid plaques build up in the brains of Alzheimer’s patients, the plaques aren’t what drive the disease and clearing them won’t help, they argue.
In the latest study for Eli Lilly’s amyloid antibody donanemab, 68% of patients were plaque-free after treatment. Yet they still deteriorated significantly and the trial missed every secondary endpoint, raising questions about whether a therapy that tried to clear more amyloid could be any more effective. Bolen acknowledged those results, but said there’s good evidence that plaques aren’t the harmful part of amyloid. Instead, it’s likely other, smaller amyloid assemblies, called fibrils and oligomers.
“Yeah, but that’s just a hypothesis,” countered Nikos Robakis, a researcher at Mt. Sinai Medical Center. They need data to support it, he said.
Robakis was the first person to clone the APP gene responsible for the genetic form of Alzheimer’s and he’s long been critical of the amyloid hypothesis. He criticized the common Alzheimer’s model Kipnis used.
To simulate the neurodegenerative disease, Kipnis had bred mice to over-express mutant proteins associated with the disease. But creating a mouse brain with too much protein isn’t the same as making an Alzheimer’s brain, Robakis said. It’s possible that over-expressed protein are what’s damaging the drainage system rather than the underlying biology you’d see in humans. The investigators, he said, need to have a control to sus out the difference — mice, for example, that have over-expressed healthy proteins, instead of over-expressed mutants.
Lipton defended the Kipnis model, noting that it’s a common one in Alzheimer’s research and patients do indeed show elevated levels of amyloid expression. He offered his own critique, though: It relies on immune cells in mice, but recent research from Lipton’s lab points to fundamental differences between human and mouse immune cells when it comes to Alzheimer’s and how they respond to amyloid-clearing antibodies.
“Hence, this new approach still will not address the intense neuroinflammation observed in human but not mouse brain (immune cells),” he said.
Kipnis’ technology doesn’t necessarily hinge on amyloid beta. In an email, he said his approach could boost anti-amyloid therapies by helping clear out the potentially toxic particles that amyloid dissolves into after an antibody binds to it. But he also noted that it could help in other ways: For example by helping restore key structures like the blood-brain barrier or clear out immune cells called microglia that contribute to harmful inflammation.
“‘Unclogging’ the drain, does not only help with more efficient plaque removal, but actually shows an improvement in other aspects of brain physiology,” he said. “That is why we think that a synergistic approach of immunotherapy+lymphatic enhancer may be more effective than any of them alone.”
Bolen also acknowledged the potential to use the new approach with therapies outside of amyloid therapies. Some critics of the amyloid hypothesis agree. Rachael Neve, director of the Gene Technology Core at MIT’s researcher and Robakis’ longtime collaborator, said in an email that improving the brain’s drainage system was a promising approach.
“It’s a beautiful paper except for their attempt to tie their results to (amyloid-beta),” she said. “That the amyloidophiles have clung to the amyloid hypothesis for decades despite the fact that it has not been proven, and have refused to entertain alternative hypotheses, is one of the tragedies of modern medical research.”