Sabriel
Paul Ashton, Ph.D.
Co-Founder, CEO, and Chairman of the Board
Balamurali Ambati, M.D., Ph.D., M.B.A.
Board Member
Jayakrishna Ambati, M.D.
Co-Founder and Board Member
Parkinson's Disease
Inflammasomes & Parkinson's Disease
Parkinson's disease (PD) is a long-term, progressive, neurodegenerative disease affecting approximately 1 million people in the US and generally occurring in people over 60 years of age. It is characterized by death of cells in the substantia nigra of the brain, leading to a reduction in levels of dopamine. Clinical symptoms include tremors, stiffness, and slow movement.
The precise cause of Parkinson's disease is unknown, although genetics and environmental exposures are implicated. Like many other neurodegenerative diseases, PD is thought to be a multi-factorial disease with many neurotoxins found in the brains of patients with the disease. Amongst these, the protein α-synuclein is considered a key protein and a target for drug development. However, also present at high levels are various forms of complement, iron accumulation, retrotransposons, gamma interferon, and reactive oxygen species. There is increasing evidence that these agents all contribute to the neuroinflammation that characterize PD.
All these neurotoxic elements, including α-synuclein, induce inflammasome activation, and markers of inflammasome activation (IL-1β, IL-18, and caspase-1) are elevated in the CSF of patients with Parkinson’s disease. Systemic levels of α-synuclein and markers of inflammasome activation are correlated with motor severity and progression of disease.
While targeting a specific element (such as α-synuclein) may be successful, we believe that inflammasome activation, the common pathway for neuroinflammation that the various toxins cause, may be a more promising approach.
References
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Blum-Degan D et al. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 1995;202(1-2)17-20
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Diaz V et al. The role of oxidative stress in Parkinson’s disease. J Parkinson's disease 2013;3(4):461-469
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Fan Z et al. Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuro Inflamm 202017:11
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Ferrari DP, Bortolanza M Del Bel EA Interferron gamma’s involvement in the neuroinflammation associated with Parkinson’s disease and L-Dopa induced dyskinesia. Neuro Tox. Res. 2021 Jun;39(3):705-719
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Gomez-Benito M et al. Modelling Parkinson’s disease with alpha synuclein protein. Front Pharmacol 2020;11:356
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Loeffler DA Camp DA and Vonant SB. Complement activation in Parkinson’s disease substantia nigra: an immunocytochemical study. J Neuroinflamm 2006;3:29
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Marras C et al. Prevalence of Parkinson’s disease in North America 2018 ;4:21
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Plaff AL et al. An increased burden of highly active retrotransposition competent L1s is associated with Parkinson’s disease risk and progression in the PPMI cohort. Int. J Mol Sci. 2020;21(18):6562
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Qin X-Y et al. Aberrations in peripheral inflammatory cytokine levels in Parkinson’s disease. A systematic review and meta analysis. JAMA Neurol. 2016;73(11)1316-1324
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Research and Markets. Parkinson’s disease drugs. Global market trajectory and analytics 2021
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Wolozin B et al. Iron and Parkinson’s disease. Neuroscientist 2002 8(1):22-32
Market Opportunity
Parkinson’s disease affects approximately 1 million people in the US. The drugs used to treat it are designed to supplement dopamine levels and hence mask the symptoms but do not affect the progression of the disease. Unfortunately, as the disease progresses these drugs become less effective. The drugs used (formulations of L-DOPA and monoamine oxidase inhibitors) have been off-patent for many years and are relatively inexpensive. The total US drug sales for PD was $1.4B in 2020, while the annual direct cost of medical care for patients with PD exceeded $25B. A drug therapy that reduces or prevents the progression of the disease (and reduces overall care costs) would be extremely valuable.
Macular Degeneration
References
- Asgari E, Le Freic G, Yamamoto H et al. C3a modulates IL-1b secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 2013; 122:3473-81.
- Boyd K and Janigian RH, Age-related macular degeneration. Am. Acad. Ophthalmol. 2018; May 17
- Brandstetter C, Holz FG, Krohne TU. Complement Component C5a Primes Retinal Pigment Epithelial Cells for Inflammasome Activation by Lipofuscin-mediated Photooxidative Damage. J Biol Chem. 2015; 290:31189-98.
- Brandstetter C, Patt J, Holz FG, et al. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B. 2016; 161:177-83.
- Cao S, Wang JC, Gao J, et al. CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation. Br J Ophthalmol. 2016; 100:713-8.
- Fowler BK, Gelfand BD, Kim Y, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 2014 Nov 21:346(6212) 1000-3.
- Gao J, Cui JZ, To E, Cao S and Matsubara JA. Evidence of the activation of pyroptotic and apoptotic pathways in RPE cells associated with NLRP3 inflammasome in the rodent eye. Amyloid- β, J Neuroinflammation 2018; 15(1):15.
- Gao, J, Liu RT, Cao S et al. NLRP3 Inflammasome activation and regulation in age-related macular degeneration. Mediators Inflamm. 2015; 690243.
- Gelfand BD, Wright C, Kim Y, et al. Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome. Cell Rep. 2015; 11:1686-93.
- Gnanaguru G, Choi AR, Amarnani D, D'Amore PA. Oxidized Lipoprotein Uptake Through the CD36 Receptor Activates the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells. IOVS 2016; 57:4704-12.
- Goldberg EL, Dixit VD. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015; 265:63-74.
- Kerur N, Fukuda S, Banerjee D, et al. cGAS drives non-canonical NLRP3 inflammasome in age-related macular degeneration. Nat Med. 2018; 24:50-61.
- Kerur N, Hirano Y, Tarallo V, et al. TLR independent and P2X7 dependent signaling regulates Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. IOVS 2013; 54:7395-401.
- Kim Y, Tarallo V, Kerur N, et al. DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. PNAS 2014; 111:16082-7.
- Kaneko H, Dridi S, Tarallo V, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011; 471:325-30.
- Laudisi F, Spreafico R, Evrard M et al. Cutting edge: the NLRP3 inflammasome links complement mediated inflammation and IL-1β . J Immunol. 2013; 191:1006-10.
- Liao Y, Zhang H, He D, et al. Retinal Pigment Epithelium Cell Death Is Associated with NLRP3 Inflammasome Activation by All-trans Retinal. IOVS 2019; 60:3034-45.
- Liu RT, Gao J and Cao S et al. Inflammatory mediators induced by amyloid beta in the retina and RPE in vivo. Implications for inflammasome activation in age related macular degeneration. IOVS 2013; 54:2225-37.
- Mao X, Fang W, Liu Q. An emerging role of Alu RNA in geographic atrophy pathogenesis: the implication for novel therapeutic strategies. Discov Med. 2016; 22:337-49.
- Martinon F, Burns K and Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspase and processing of pro IL-beta. Mol Cell. 2002;10:417-26.
- Mao X, Pan T, Shen H et al. The rescue effect of mesenchymal stem cell on sodium iodate induced retinal pigment epithelial cell death through deactivation of NF-KB mediated NLRP3 inflammasome. Biomed Pharmacother. 2018;103:517-23.
- Mizutani T, Fowler BJ, Kim Y, et al. Nucleoside reverse transcriptase inhibitors suppress laser-induced choroidal neovascularization in mice. IOVS 2015; 56: 7122-9.
- Nozaki M, Raisler BJ, Sakurai E et al. Drusen complement components C3a and C5a promote choroidal neovascularization. PNAS 2006; 103:2328-33.
- Prager P, Hollborn M, Steffen A, Wiedemann P, Kohen L, Bringmann A. P2Y1 Receptor Signaling Contributes to High Salt-Induced Priming of the NLRP3 Inflammasome in Retinal Pigment Epithelial Cells. PLoS One. 2016;11(10):e0165653.
- Tarallo V, Hirano Y, Gelfand BD, et al. Loss of DICER1 loss and Alu RNA induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88. Cell 2012; 149: 847-59.
- The Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004; 122:564-72.
- Wang Y, Hanus JW, Abu-Asab MS, et al. NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration. Int J Mol Sci. 2016; 17(1). pii: E73.
- Wang K, Yao Y, Zhu K et al. Amyloid β induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production. J Biochem Mol Toxicol. 2017; 31(6).
- Wong et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2014; 2:e106-16.
- Young BM, Jones K, Massengill MT, et al. Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model. Mol Ther Methods Clin Dev. 2019; 14:113-25.
Market Opportunity
The total number of patients with GA in the US, 1 million (The eye disease prevalence research group, 2004), is similar to the number of patients with wet AMD, for which there are currently three dominant treatments: Lucentis (Roche), Eylea (Regeneron), and off-label use of the anti-cancer drug, Avastin. Annual sales of these products exceeded $5B in the US in 2017 (GlobalData, 2018). These drugs all target vascular endothelial growth factor (VEGF), which is one of the key cytokines responsible for the development of wet AMD. VEGF is not thought to be involved in dry AMD and these drugs have no effect on dry AMD, including on its most serious form, GA. There is no approved treatment for GA or other forms of dry AMD.
Global AMD revenue in 2015 was $5.3B, driven by Eylea, Lucentis, and Avastin (off label) for wet AMD. The Expected AMD CAGR of 7.6% during 2016-2022 due to the growing aged population and increasing prevalence of lifestyles related factors such as obesity and hypertension. Additional AMD treatments are expected to increase growth.
Multiple Sclerosis
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
Alzheimer's Disease
Inflammasomes & Alzheimer's Disease
Alzheimer's Disease is the most common form of dementia, affecting 5.7M people in the US and 1 in 10 people over 70 years of age. There are no satisfactory treatments for the disease.
It has long been recognized that in AD, amyloid-β and tangles of tau protein accumulate in the brain, triggering inflammation and nerve cell death, which then triggers further inflammation and amyloid-β accumulation.
Biochemically, AD is a multifactorial disease. Amyloid-β and tau protein tangles have long been therapeutic targets in the AD as they are present in the brains of patients with AD. Also present in brains of patients with the disease are elevated levels of Alu-RNA, complement, iron, and reactive oxygen species. These different factors all induce inflammasome activation, which triggers production of caspase-1 and the inflammatory cytokines, IL-1β and IL-18. In AD, inappropriate inflammasome activation causes nerve cell death.
In animal studies it has been found that inhibition of caspase-1 and inflammasome activation alleviates cognitive impairment and neuropathy in an Alzheimer’s disease mouse model.
References
- Ahmed M, Iyer S, Thangavel R, et al. Co-localization of glia maturation factor with NLRP3 inflammasome and autophagosome markers in human Alzheimer’s disease brain. J Alzheimer’s Dis. 2017; 60:1143-1160.
- Alzheimer’s Association. 2019 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2019; 15:321-87.
- Chakraborty S, Kaushik DK, Gupta M, et al. Inflammasome signaling at heart of central nervous system pathology. J Neurosci Res. 2010; 88:1615-31.
- Cully M. Inflammasome protein seeds plaques in Alzheimer’s disease. Nature Rev Drug Discov. 2018; 17:96.
- Dempsey C, Rubio Araiz A, Bryson KJ, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017; 61:306-16.
- Flores J, Noel A, LeBlanc AC et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathy in an Alzheimer’s disease mouse model. Nat Commun. 2018;9:3916.
- Gold M and El-Khoury J. β-amyloid, microglia and the inflammasome in Alzheimer’s disease. Semin Immunopathol. 2015; 37:607-11.
- Halle A, Hornung V, Petzold GC, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008; 9:857-65.
- Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493:674-8.
- Lane DR, Ayton S and Bush A. Iron and Alzheimer’s Disease: an update on emerging mechanisms. J Alzheimers Dis. 2018; 64(s1) s379-s395.
- Larsen PA, Lutz MW, Hunnicutt KE et al. The Alu neurodegeneration hypothesis: a primate specific mechanism of neuronal transcriptional noise, mitochondrial dysfunction and manifestation of neurodegenerative disease. Alzheimers Dement. 2017; 13:828-38.
- Liu L and Chan C. The role of inflammasome in Alzheimer’s disease. Aging Res Rev. 2014; 15:6-15.
- Morgan BP. Complement in the pathogenesis of Alzheimer’s disease. Semin Immunopathol. 2018; 40:113-24.
- Polesskaya O, Kananykhina E, Roy-Engel AM, et al. The role of Alu-derived RNAs in Alzheimer's and other neurodegenerative conditions. Med Hypotheses. 2018; 115:29-34.
- Saresella M, La Rosa F, Piancone F, et al. NLRP2 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol. Neurodegener. 2016; 3:11-23.
- Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013; 14:812-20.
- Stancu IC, Cremers N, Vanrusselt H, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019; 137:599-617.
- Tan MS, Yu JT, Jiang T, et al. NLRP3 polymorphisms are associated with late-onset Alzheimer's disease in Han Chinese. J Neuroimmunol. 2013; 265:91-5.
- Tejera D, Mercan D, Sanchez-Caro JM, et al. Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome. EMBO J. 2019;38:e101064.
- White CS, Lawrence CB, Brough D, et al. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 2017; 27:223-34.
Market Opportunity
In 2017 global Alzheimer's Disease revenue was $3.6B, driven by Aricept, Exelon and Razadyne. According to Zion Market Research the expected CAGR for AD drugs between 2017-2024 is 8% due to the growing aged population and the increasing prevalence/diagnosis of AD. However, PharmaPoint reports that additional AD treatments could increase market growth to 17% CAGR for a global market to exceed $12B by 2026.
- Alzheimer’s drug market 2017-2024, Zion Market Research
- PharmaPoint: Alzheimer’s disease global drug forecast and market analysis to 2026. GlobalData 2017