The rare monogenic disease Familial Mediterranean Fever (FMF) is driven by mutations that impact pyrin, a canonical inflammasome distinct from NLRP3. A subset of Pyoderma Gangrenosum (PG) patients also carry a monogenic mutation that results in activation of pyrin. PG is characterized by neutrophilic skin inflammation and inflammasome activation, suggesting that Gasdermin D inhibition may provide a new thereapy for this severe disease.
Rheumatoid arthritis (RA) and lupus patients are characterized by displaying high levels of NETosis – the inflammatory cell death of neutrophils. Multiple inflammasome proteins and polymorphisms in IL-18 are associated with lupus. While current therapies are efficacious for some RA patients, significant unmet need remains in both diseases. We believe an inhibitor of GSDMD will address the drivers of these diseases.
Neuroinflammation is a core driver of multiple sclerosis (MS). Recent studies have demonstrated that both the canonical and non-canonical inflammasome pathways are drivers of inflammation in MS patients and in animal models of MS. We believe inhibiting GSDMD provides promise to interfere with both of these pathways.
The lung inflammation of severe asthmatics who respond poorly to therapy has been linked to increased NETosis. Inflammatory cytokine IL-18 is also genetically associated with asthma risk. We expect a GSDMD inhibitor to block both NETosis and IL-18 release.
The hepatic diseases nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis are driven by both the canonical and non-canonical inflammasome pathways. We believe a GSDMD inhibitor will interfere with both of these pathways.