Two groundbreaking studies have reinforced the critical role of microglial inflammation in Parkinson's disease (PD) progression and validated ZyVersa Therapeutics' Inflammasome ASC Inhibitor IC 100 as a promising disease-modifying treatment candidate.
The research, published in npj Parkinson's Disease and Experimental and Molecular Medicine, both peer-reviewed journals from Nature, demonstrates that IC 100 can effectively reduce microglial inflammasome activation and improve clearance of toxic phosphorylated alpha-synuclein—key contributors to neurodegeneration in PD.
"These are the first data to link ASC speck assembly, NLRP1 inflammasome activation, and alpha-synuclein aggregation in neurons of Parkinson's disease patients," said Stephen C. Glover, ZyVersa's Co-founder, Chairman, CEO and President. "IC 100, which unlike NLRP3 inhibitors, targets ASC, ASC specks, and multiple types of inflammasomes, blocked microglial NLRP1 inflammasome activation and reduced alpha-synuclein accumulation."
The Microglial Inflammation Connection
The first study, conducted by researchers at the University of Miami Miller School of Medicine and supported by a grant from the Michael J. Fox Foundation, revealed several critical findings:
- ASC and NLRP1 were present in the core of alpha-synuclein in neuronal Lewy bodies of PD patients
- Granular neuron loss was observed in PD patient tissues
- ASC specks from PD patient brains triggered inflammasome activation and cell death in human microglia, which was blocked by IC 100
- IC 100 altered the cellular distribution and decreased levels of phosphorylated alpha-synuclein, indicating improved clearance of pathogenic alpha-synuclein
The second study further validated these findings, demonstrating that microglial-driven inflammation alone can trigger the full range of pathological features observed in neurodegenerative diseases. Key observations included:
- Microglial cells stimulated by alpha-synuclein or tau shifted from homeostatic to an activated inflammatory state
- Transplanting inflammatory microglia into the striatum of naive mice resulted in abnormal accumulation of alpha-synuclein or tau, severe gliosis, and neuroinflammation
- Progressive spreading of pathological changes beyond the injection site
- Progressive motor and cognitive deficits in the mice
"We are thrilled to see a second study substantiating the critical need to control microglial inflammation to attenuate development and progression of Parkinson's disease," Glover noted. "Together, results from the two studies strengthen the evidence that IC 100 has potential to become a disease-modifying therapy for PD."
IC 100: A Novel Approach to Treating Parkinson's
Parkinson's disease affects over 10 million people globally and is characterized by progressive neurodegeneration resulting in impaired mobility, cognitive decline, and other neurological symptoms. Current treatments address only symptoms—not the underlying disease pathology—and generated $6.6 billion globally in 2024, with projections to reach $13.3 billion by 2034, according to Precedence Research.
IC 100 represents a novel approach to treating PD. It is a humanized IgG4 monoclonal antibody that inhibits the inflammasome adaptor protein ASC. The therapy was designed to attenuate both initiation and perpetuation of the inflammatory response by:
- Binding to a specific region of the ASC component of multiple types of inflammasomes, including NLRP1, NLRP2, NLRP3, NLRC4, AIM2, and Pyrin
- Binding to ASC monomers intracellularly, inhibiting inflammasome formation
- Binding to ASC in ASC Specks, both intracellularly and extracellularly, further blocking activation of IL-1β
"Our findings demonstrate that targeting inflammasomes and ASC specks may be a promising approach not only for PD but also for Lewy body dementia and Alzheimer's Disease," said Dr. Robert W. Keane, Professor at the University of Miami and lead author of the first study. "IC 100's mechanism, which uniquely inhibits both ASC speck activity and misfolded protein aggregates, makes it a strong candidate for treating neurodegenerative diseases."
Looking to the Future
ZyVersa is preparing to initiate proof-of-concept studies in PD animal models later this year. While IC 100's lead indication is currently obesity with certain metabolic complications, these findings suggest significant potential for expanding its application to neurodegenerative diseases.
The company is well-positioned in the rapidly emerging inflammasome space with IC 100, and also has a phase 2 Cholesterol Efflux Mediator™ VAR 200 in development for kidney disease. ZyVersa estimates its total accessible market at over $100 billion.
As research continues to validate the critical role of inflammation in neurodegenerative diseases, therapies like IC 100 that target underlying disease mechanisms rather than just symptoms could represent a significant advancement in the treatment of Parkinson's disease and related conditions.
