Inflammasomes & Multiple Sclerosis
Multiple Sclerosis is a disabling disease of the central nervous system (CNS) affecting approximately 900,000 people in the US. It is an autoimmune disease in which the immune system attacks and destroys the myelin sheath that protects nerve fibers in the brain and spinal cord. The causes of MS are unknown but it is associated with smoking, viral infection (Epstein Barr), other autoimmune diseases, and heredity. It is 3 times more common in women and usually diagnosed between the ages of 16 and 55.
Inflammasome activation is recognized as being pathogenic in Multiple Sclerosis. Inflammasome activation causes production and release of caspase-1 and inflammatory cytokines, IL-1β and IL-18. Caspase-1 and these cytokines are elevated in peripheral monocytes, CSF, or serum of patients with MS and are increased further either during or immediately preceding disease flare ups. Elevations of these inflammatory markers are predictive of clinical progression of the disease, while in animal models their inhibition prevents disease progression. These findings indicate a crucial role of inflammasome activation in the pathology of MS.
References
- Barclay W and Shinohara ML. Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Brain Pathol. 2017; 27:213-219.
- Furklan R, Flippi M Bergami A et al. Peripheral levels of caspase-1 mRNA correlate with disease activity in patients with multiple sclerosis; a preliminary study. J Neurol Neurosurg and Psychiatry 1999; 67:785-8.
- Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015; 21:248-55.
- Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, Huang M, Schneider M, Miller SD, Ting JP. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol. 2010; 185:974-81.
- Heinrich MJ, Purcell CA, Pruijssers AJ, et al. Endogenous double-stranded Alu RNA elements stimulate IFN-responses in relapsing remitting multiple sclerosis. J Autoimmun. 2019; 100:40-51.
- Jha S, Srivastava, SY, Brickey WJ, et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci. 2010; 30:15811-20.
- Keene RW, Dietrich WD and de Rivero Vaccari JP. Inflammasome Proteins as Biomarkers of Multiple Sclerosis. Front Neurol. 2018; 9:135
- McKenzie BA, Mamik MK, Saito LB et al. Caspase-1 inhibition prevents gial inflammasome activation and pyroptosis In models of multiple sclerosis. PNAS 2018; 115:E6065-E6074
- Nicolleti F, Di Marco R Mangano K et al. Increased serum levels of interleukin-18 in patients with multiple sclerosis. Neurology 2001; 57:342-4
- Rossi S, Sturder V, Motta C. Cerebrospinal fluid detection of interleukin-1β in phase remission predicts disease progression in multiple sclerosis. J Neuroinflammation 2014; 11:32
- Soares JL, Olivera EM and Pontillo A. Variants in NLRP3 and NLRC4 inflammasome associate with the susceptibility and severity of multiple sclerosis. Mult Scler Relat Disord. 2019; 29:26-34.
- Voet S, Mc Guire C, Hagemeyer N, et al. A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation. Nat Commun. 2018; 9:2036.
- Vidmar L, Maver A, Drulović J, et al. Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes. Sci Rep. 2019; 9:9171.
- Wallin MT, Culpepper WJ Campbell JD et al. The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology 2019; 92:e1029-e1040
Market Opportunity
The 2018 global Multiple Sclerosis market is estimated to be valued at over $20B, with expected CAGR for MS drugs is 2.5% reaching sales of over $25B by 2026. It is a competitive market dominated by Roche’s Ocrevus (Roche), Gilenya (Novartis) and Tecfidera (Biogen) together generating over $10B in sales. Although large, the market is not expected to grow quickly due to patent expirations and difficulty in product differentiation.
- MarketWatch Jan 2019
- Pharmaceutical Technology: Moderate growth in the multiple sclerosis market. March 2018