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.