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Parkinson’s drug makers target inflammasome

Link to α-synuclein builds case for inflammasome targeting to treat Parkinson’s disease.
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Hyperstimulated immune cells in the brain are emerging as a hallmark feature of most neurodegenerative disorders—and Parkinson’s disease is no exception. In patients with the progressive movement disorder, those immune cells, called microglia, react to the presence of α-synuclein-containing protein clumps by dialing up inflammatory signals that not only contribute to the gradual death of dopamine-producing neurons but also recruit more pathological proteins, creating a vicious cycle of neuroinflammation and α-synuclein buildup in the brain.

The inflammasome could be driving the progressive neuronal loss seen in the brains of Parkinson’s disease patients. (Credit: BSIP SA / Alamy Stock Photo).

To break the cycle, a Dublin-based startup called Inflazome is aiming to disrupt the NLRP3 inflammasome, a multiprotein complex that serves as a sensor of cell stress and abnormal proteins. Last year, the company’s founders—Matt Cooper, a chemist from the University of Queensland in Brisbane, Australia, and Luke O’Neill, an immunologist at Trinity College Dublin—demonstrated a clear link between α-synuclein aggregation and inflammasome activation in the brain microglia of mice with a Parkinson’s-like condition. Most notably, they showed the defect could be remedied with an NLRP3 inhibitor called MCC950.

“We knew that inflammation and microglial activation were involved in this disease, so we were expecting benefit, but the degree of protection we observed was quite profound,” says Trent Woodruff, a neuroimmunologist at the University of Queensland who co-led the study. “That really said to us that the underlying driver of neuronal death, at least in these preclinical models, is really the activation of the immune system at these inflammatory pathways.”

In recent weeks, Inflazome completed a €40 million ($46 million) series B financing round to advance a range of small-molecule drugs targeting the NLRP3 inflammasome to treat diseases driven by persistent, low-level inflammation. The company also hired Thomas Jung, formerly at Novartis leading the development of Illaris (canakinumab), an interleukin-1β inhibitor for childhood arthritis and rare fever syndromes, as its new chief medical officer.

According to Cooper, who serves as CEO, Inflazome will likely first pursue an indication outside of the central nervous system; but, of the 54 diseases on the company’s long list, Parkinson’s remains a top priority.

Drug companies’ efforts to squelch chronic inflammation had focused initially on blocking interleukin-1β signaling (Nat. Biotechnol. 28, 533–534, 2010. And in fact, the Pfizer scientists who originally discovered MCC950 assumed that was how the molecule worked when, around the turn of the century, they took the drug into clinical trials as a treatment for rheumatoid arthritis. (The development program stopped after phase 1b testing.)

But four years ago, Cooper and O’Neill established that MCC950 is actually a specific inhibitor of the NOD-like receptor family pyrin-domain-containing protein 3 (NLRP3) inflammasome. Their report set off a flurry of activity—both commercial and academic—around the idea of targeting the inflammasome complex to treat a wide range of disorders. By testing MCC950 in assorted mouse models, researchers around the world showed that NLRP3 blockade can help attenuate asthma, neuropathic pain, colitis, stroke, chikungunya infection and more—including Parkinson’s.

Molecular biologist Olga Corti has also looked into MCC950 as a potential Parkinson’s treatment. She and her colleagues at the ICM Brain & Spinal Institute in Paris derived macrophages from the blood of patients with parkin mutations, the most common genetic cause of early-onset Parkinson’s disease. In a paper published last April, they showed that those immune cells displayed exaggerated NLRP3 responses—aberrant inflammation that could be reversed by the drug treatment.

Adding legitimacy to the strategy are findings from post-mortem brain tissue taken from people who died after being diagnosed with the disease. In independent reports last year, both the Inflazome-affiliated team from Australia and another group led by neurobiologist Matthew Havrda from the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire, documented high levels of key inflammasome components in the substantia nigra, home to the dopamine-producing neurons most affected by the disease.

In Havrda’s report, he and graduate student Katharine von Herrmann also identified a point mutation in the NLRP3 gene that seemed to confer protection against Parkinson’s. The mutation didn’t alter the resulting amino acid sequence. Rather, the synonymous variant seemed to make translation less efficient, leading to reduced NLRP3 production and about a 50% lower risk of disease. “If you have this variant, as rare as it is, you’re more likely to avoid the perils of Parkinson’s,” Havrda says.

In another study, Havrda and his student Faith Anderson looked for inflammasome proteins circulating in the blood plasma of people with and without Parkinson’s. “These should never be outside the cells,” Havrda explains, but can get shed into the bloodstream during pyroptosis, an inflammatory form of programmed cell death. Early, unpublished findings indicate that individuals with Parkinson’s show elevated levels of NLRP3, gasdermin, caspase-1 and other parts of the inflammasome complex.

That finding dovetails with what Anumantha Kanthasamy, a molecular neurotoxicologist at Iowa State University in Ames, described in January. He and his colleagues showed that manganese, a chemical element known to be an occupational hazard for developing Parkinson’s, increased NLRP3 inflammasome expression and activation in microglial cells and that exosomes found in the blood of welders exposed to manganese fumes contained elevated levels of ASC, a key inflammasome protein.

“We’re slowly building the target validity for NLRP3,” says Kuldip Dave, a director of research programs at the Michael J. Fox Foundation for Parkinson’s Research in New York City, which supports the Queensland, Dartmouth and ICM groups. Other drug strategies have entered clinical testing for Parkinson’s with much less of a scientific rational, he notes. NLRP3 inhibition should thus be trialed in patients. “This is ready,” Dave says.

Cooper hopes to launch a Parkinson’s trial sometime next year with one of Inflazome’s next-generation NLRP3 inhibitors. In mouse models of the disease, several of these molecules has shown greater efficacy than MCC950, he says.

Meanwhile, other companies with NLRP3 inhibitors in the pipeline have elected to concentrate instead on peripheral diseases—in particular, liver fibrosis and its extreme manifestation, nonalcoholic steatohepatitis. That strategy paid off for Jecure Therapeutics, a startup focused on liver disease that got scooped up late last year by Genentech for an undisclosed sum of money.

NodThera, another developer of NLPR3 blockers, will likely move into clinical testing for fibrosis, says Adam Keeney, president and CEO of the Cambridge, UK–based company. But “we are very interested in Parkinson’s,” he adds. And although IFM Therapeutics CEO Gary Glick says his company is more interested in Alzheimer’s disease than Parkinson’s, he’s quick to note that “the target has a wealth of virtues for a whole range of indications.”

doi: 10.1038/d41587-019-00005-8
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