Welcome to the Inflammasome
Published 8/23/2022
What is the inflammasome? It is part of the immune system responsible for the activation of inflammatory responses: a multiprotein cytoplasmic complex that includes a sensor, and adapter, and an effector. (1) In the case of the NLRP3 inflammasome, among others, the effector is the enzyme caspase-1, which activates the proinflammatory cytokine IL-1β.
When working well, inflammasomes ensure that bodily damage is repaired through its own mechanisms and via immune mediation. (2) But, as often happens, things go wrong, leading often to chronic inflammation and disease, turning the body into a battleground of its own making.
We've known since 2001 of the inflammasome’s role in cryopyrin associated periodic syndrome aka CAPS, (3) and since 2013 of its role in age-related macular degeneration, with drug development heading towards targeting NLRP3 (4). Beyond these, the inflammasome also plays a role in cardiovascular and neurologic disease. The NLRP3 inflammasome can be activated by a variety of risk factors that play critical roles in myocardial infarction, heart failure, (5) and multiple sclerosis. (6)
CAPS is a pure model of inflammasome-mediated disease, caused by gain of function mutations in genes that code for the NLRP3 inflammasome, (7) that result in overproduction of IL-1β. CAPS is effectively treated with anti-IL-1β drugs but these drugs have shortcomings such as the need for regular injections. (8)
A hero might be on the horizon, however.
Ventyx recently released very promising phase 1 data on VTX2735, a targeted oral NLRP3 therapy. In their press release, Ventyx stated that “VTX2735 demonstrated robust dose-related suppression of the induced pro-inflammatory cytokine IL-1β release relative to placebo.” With only mild side effects, VTX2735 could be a boon for CAPS patients and those with related autoinflammatory diseases. (9)
Another company contending for pharma-based inflammasome dominance is Zyversa, with their multi-inflammasome inhibitor, monoclonal antibody IC100. IC100 targets the protein ASC, which is found in several different inflammasomes. Promising preclinical research conducted by Drs. Robert W Keane and Juan Pablo de Rivero Vaccari of the University of Miami Miller School of Medicine. According to Dr. Keane, “IC 100 gains access into cells…inhibiting activation and release of IL-1 β….” Other work showed that IC100 (10) reduced immune cell penetration of the spinal cord and had functional benefit in a study of mice with EAE, a model of multiple sclerosis. (11)
So, let’s control the inflammasome!
Resources
1- Nature Reviews Immunology: The NLRP3 inflammasome: molecular activation and regulation to therapeutics
2- News-Medical.Net: What is the Inflammasome?
3- NBBI NLM: The inflammasome, an innate immunity guardian, participates in skin urticarial reactions and contact hypersensitivity
4- NIH: Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle– Wells syndrome
5- The Scientist: Pharma Looks to Inflammasome Inhibitors as All-Around Therapies
6- Frontiers in Molecular Neuroscience: Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics
7- HHS: CAPS and NLRP3
8- NIH: Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle – Wells syndrome
9- Ventyx Bioscience: VENTYX BIOSCIENCES Announces Positive Topline Phase 1 Data For Its Peripheral NLRP3 Inhibitor VTX2735
10- AP News: ZyVersa’s Proprietary Inflammasome ASC Inhibitor’s Differentiated Mechanism of Action Featured in Translational Research Paper
11- Springer Nature: IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis
12- The Scientist: Pharma Looks to Inflammasome Inhibitors as All-Around Therapies