Halia Therapeutics, NodThera and Gain Therapeutics target neuroinflammatory processes in hopes of modifying the course of Parkinson’s progression.
Preventing or reversing neuroinflammation could be the next clinical frontier in treating Parkinson’s disease, according to recent research and experts familiar with the biology of the phenomenon.
Several biopharmaceutical companies—including NodThera, Halia Therapeutics, Gain Therapeutics and Olatec—are aiming to halt the neuroinflammatory cycle that contributes to Parkinson’s.
Neuroinflammation has also piqued the interest of Alzheimer’s researchers, with companies such as Vigil Neuroscience and Cerevance targeting the TREM2 protein and KCNK13 gene, respectively.
“This is one of the ways the field is moving now,” said Alan Watt, president and chief scientific officer at NodThera. “The anti-inflammatory component—not just in Parkinson’s, but in all of these neurodegenerative diseases—is now getting recognized as a key driver of the progression.”
The Never-Ending Loop
While people largely think of inflammation as the body’s protective response to infection or trauma, when it comes to Parkinson’s, “what we’re interested in is when inflammation goes wrong,” Watt told BioSpace.
Chronic low-grade inflammation can damage the brain’s neurons and cause cell death, he explained, adding that NodThera hopes to intervene and block this with therapy.
Chronic inflammation “plays a role in almost every chronic disease that you can think of,” agreed David Bearss, CEO of Halia Therapeutics.
NodThera and Halia are among the companies exploring drug candidates that target the inflammasome NLRP3, a contributor to many neurodegenerative diseases. NLRP3 is a first responder of sorts that can notify the rest of the body when something is wrong in the brain, triggering microglia to stimulate the inflammatory response to take care of the issue, Bearss said. However, a problem doesn’t always exist.
“When cells get activated and recruited to come and try to find something, if they can’t find a problem, they actually create the problem,” Bearss explained. “They’ll say, ‘I got called to come here for a reason. There must be something wrong.’”
This response then gets stuck in a loop, becoming stronger over time and leading to neurodegenerative conditions, he said. “Over the past 10 years, we’ve started to realize that chronic inflammatory signaling in the brain drives [neurodegenerative] conditions. There’s nothing good that happens when you get inflammation in your brain.”
Breaking the Inflammatory Cycle
Halia is investigating a NEK7/NLRP3 inhibitor that could break the chronic inflammatory cycle. NEK7 is a protein involved in the assembly of the NLRP3 inflammasome that triggers chronic inflammation. Phase I studies showed this drug candidate could prevent assembly of the inflammasome and help disassemble the fully formed inflammasome complexes in Parkinson’s disease.
By ending this process, disease progression could be stopped—and maybe even reversed, Bearss said. “We’re very encouraged by the idea that eliminating this chronic signaling might be able to not just stop the progression of the disease but even allow the brain to start to repair itself.”
Stopping NLRP3 and microglial dysfunction is also the goal of NodThera, which reported Phase II results of its NLRP3 inhibitor in March. Patients in all stages of Parkinson’s disease were given the drug for 28 days; samples of blood and cerebrospinal fluid taken at day 28 showed the inflammatory chemical levels far below those of day 1—near those of healthy elderly adults without Parkinson’s disease. Reductions were also seen in the neurodegenerative markers neurofilament light chain and soluble TREM2.
Bearss and Watt each noted that more research is needed to determine whether either drug can reverse motor symptoms of Parkinson’s. NodThera’s next ambition is another Phase II study to track motor symptoms for six months. “At the least, we hope to be at sort of a slow progression. At best, you’d love to be at a hold progression—or even see some sort of neuro-regeneration actually going on and improve the symptomatology,” Watt said.
Bearss emphasized the potential of breaking the neuroinflammatory cycle. “There is data coming out now that if . . . you can break that cycle, our body and our brains have a way to repair themselves that I think we still don’t completely understand,” he said.
Targeting GBA1 in Parkinson’s Disease
Another way to possibly stop neuroinflammation in Parkinson’s disease is by targeting a lysosomal enzyme called glucocerebrosidase (GCase). The dysfunctional version of this enzyme is the result of mutations in the GBA1 gene, which is the leading genetic risk factor for developing Parkinson’s, according to Joanne Taylor, senior vice president of research for Gain Therapeutics. Gain is developing GT-02287, an allosteric protein modulator that restores the function of GCase.
“We have shown in various preclinical models of Parkinson’s disease that by targeting GCase and correcting its function with GT-02287, we can address many of the downstream pathophysiological features seen in GBA1 Parkinson’s disease,” Taylor told BioSpace in an email.
Disease Modification Is the Future
Modifying the course of the disease rather than treating the symptoms is the future of Parkinson’s treatment, the researchers agreed.
“If you look at the Parkinson’s market right now, there are no disease-modifying therapies,” Watt said. “Everything is there to treat symptoms. They boost dopamine and bring relief to people, and that’s certainly a relief. But what they don’t do is change the course of the disease.”
The disease modifying approach could extend to treating patients before the disease presents itself, Taylor predicted. “As we continue to understand more and more about the molecular mechanisms underlying the disease process, we are able to target those specific mechanisms. . . . The dream is to eventually be able to treat future patients before the disease manifests itself so that patients never develop the clinical features we associate with the disease.”
