COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease

References

• Pagnon de la Vega M, Naslund C, Brundin R, et al. Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer’s disease and frontotemporal dementia. BMC Genomics. 2022 Feb 4;23(1):99.
   PubMed Web of Science ®Google Scholar
• Galimberti D, Scarpini E. Genetics and biology of Alzheimer’s disease and frontotemporal lobar degeneration. Int J Clin Exp Med. 2010 May 15;3(2):129–143.
   PubMed Web of Science ®Google Scholar
• Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016 Jun;8(6):595–608.
   PubMed Web of Science ®Google Scholar
• Decourt B, D’Souza GX, Shi J, et al. The cause of Alzheimer’s disease: the theory of multipathology convergence to chronic neuronal stress. Aging Dis. 2022 Feb;13(1):37–60.
   PubMed Web of Science ®Google Scholar
• Brothers HM, Gosztyla ML, Robinson SR. The physiological roles of amyloid-beta peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci. 2018;10:118.
   PubMed Web of Science ®Google Scholar
• Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010 Mar 3;5(3):e9505.
   PubMed Web of Science ®Google Scholar
• Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement. 2018 Dec;14(12):1602–1614.
   PubMed Web of Science ®Google Scholar
• Gosztyla ML, Brothers HM, Robinson SR. Alzheimer’s amyloid-beta is an antimicrobial peptide: a review of the evidence. J Alzheimers Dis. 2018;62(4):1495–1506.
   PubMed Web of Science ®Google Scholar
• Bourgade K, Dupuis G, Frost EH, et al. Anti-viral properties of amyloid-beta peptides. J Alzheimers Dis. 2016 Oct 4;54(3):859–878.
   PubMed Web of Science ®Google Scholar
• Bourgade K, Le Page A, Bocti C, et al. Protective effect of amyloid-beta peptides against herpes simplex virus-1 infection in a neuronal cell culture model. J Alzheimers Dis. 2016;50(4):1227–1241.
   PubMed Web of Science ®Google Scholar
• Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016 May 25;8(340):340ra72.
   PubMed Web of Science ®Google Scholar
• Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018 Jul 11;99(1):56–63 e3.
   PubMed Web of Science ®Google Scholar
• Itzhaki RF. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front Aging Neurosci. 2014;6:202.
   PubMed Web of Science ®Google Scholar
• Miklossy J. Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci. 2015;7:46.
   PubMed Web of Science ®Google Scholar
• Balin BJ, Little CS, Hammond CJ, et al. Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease. J Alzheimers Dis. 2008 May;13(4):371–380.
   PubMed Web of Science ®Google Scholar
• Angel TE, Jacobs JM, Smith RP, et al. Cerebrospinal fluid proteome of patients with acute lyme disease. J Proteome Res. 2012 Oct 5;11(10):4814–4822.
   PubMed Web of Science ®Google Scholar
• Itzhaki RF, Lathe R, Balin BJ, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):979–984.
   PubMed Web of Science ®Google Scholar
• Muller U, Vogel P, Alber G, et al. The innate immune system of mammals and insects. Contrib Microbiol. 2008;15:21–44.
   PubMedGoogle Scholar
• Stein PS, Desrosiers M, Donegan SJ, et al. Tooth loss, dementia and neuropathology in the Nun study. J Am Dent Assoc. 2007 Oct;138(10):1314–1322. quiz 1381-2.
   PubMed Web of Science ®Google Scholar
• Kaye EK, Valencia A, Baba N, et al. Tooth loss and periodontal disease predict poor cognitive function in older men. J Am Geriatr Soc. 2010 Apr;58(4):713–718.
   PubMed Web of Science ®Google Scholar
• Ide M, Harris M, Stevens A, et al., Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11(3): e0151081.
   PubMed Web of Science ®Google Scholar
• Tsuneishi M, Yamamoto T, Yamaguchi T, et al. Association between number of teeth and Alzheimer’s disease using the National Database of Health Insurance Claims and specific health checkups of Japan. PLoS One. 2021;16(4):e0251056.
   PubMed Web of Science ®Google Scholar
• Xu S, Huang X, Gong Y, et al. Association between tooth loss rate and risk of mild cognitive impairment in older adults: a population-based longitudinal study. Aging (Albany NY). 2021 Sep 7;13(17):21599–21609.
   PubMedGoogle Scholar
• Qi X, Zhu Z, Plassman BL, et al. Dose-response meta-analysis on tooth loss with the risk of cognitive impairment and dementia. J Am Med Dir Assoc. 2021 Oct;22(10):2039–2045.
   PubMed Web of Science ®Google Scholar
• How KY, Song KP, Chan KG. Porphyromonas gingivalis: an overview of periodontopathic pathogen below the gum line. Front Microbiol. 2016;7:53.
   PubMed Web of Science ®Google Scholar
• Kamer AR, Pirraglia E, Tsui W, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging. 2015 Feb;36(2):627–633.
   PubMed Web of Science ®Google Scholar
• Griffen AL, Becker MR, Lyons SR, et al. Prevalence of Porphyromonas gingivalis and periodontal health status. J Clin Microbiol. 1998 Nov;36(11):3239–3242.
   PubMed Web of Science ®Google Scholar
• Flemmig TF, Milian E, Karch H, et al. Differential clinical treatment outcome after systemic metronidazole and amoxicillin in patients harboring actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis. J Clin Periodontol. 1998 May;25(5):380–387.
   PubMed Web of Science ®Google Scholar
• Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019 Jan;5(1):eaau3333.
   PubMed Web of Science ®Google Scholar
• Singhrao SK, Harding A, Poole S, et al. Porphyromonas gingivalis periodontal infection and its putative links with Alzheimer’s disease. Mediators Inflamm. 2015;2015:137357.
   PubMed Web of Science ®Google Scholar
• Castro SA, Collighan R, Lambert PA, et al. Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils. Cell Death Dis. 2017 Mar 2;8(3):e2644.
   PubMedGoogle Scholar
• Zheng S, Yu S, Fan X, et al. Porphyromonas gingivalis survival skills: immune evasion. J Periodontal Res. 2021 Dec;56(6):1007–1018.
   PubMed Web of Science ®Google Scholar
• Ishikawa M, Yoshida K, Okamura H, et al. Oral Porphyromonas gingivalis translocates to the liver and regulates hepatic glycogen synthesis through the Akt/GSK-3beta signaling pathway. Biochim Biophys Acta. 2013 Dec;1832(12):2035–2043.
   PubMed Web of Science ®Google Scholar
• Iida Y, Honda K, Suzuki T, et al. Brain abscess in which Porphyromonas gingivalis was detected in cerebrospinal fluid. Br J Oral Maxillofac Surg. 2004 Apr;42(2):180.
   PubMed Web of Science ®Google Scholar
• Mougeot JC, Stevens CB, Paster BJ, et al. Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J Oral Microbiol. 2017;9(1):1281562.
   PubMed Web of Science ®Google Scholar
• Poole S, Singhrao SK, Kesavalu L, et al., Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013;36(4):665–677.
   PubMed Web of Science ®Google Scholar
• Ilievski V, Zuchowska PK, Green SJ, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018;13(10):e0204941.
   PubMed Web of Science ®Google Scholar
• Poole S, Singhrao SK, Chukkapalli S, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis. 2015;43(1):67–80.
   PubMed Web of Science ®Google Scholar
• Diaz-Zuniga J, More J, Melgar-Rodriguez S, et al. Alzheimer’s disease-like pathology triggered by Porphyromonas gingivalis in wild type rats is serotype dependent. Front Immunol. 2020;11:588036.
   PubMed Web of Science ®Google Scholar
• Qian X, Zhang S, Duan L, et al. Periodontitis deteriorates cognitive function and impairs neurons and glia in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2021;79(4):1785–1800.
   PubMed Web of Science ®Google Scholar
• Ishida N, Ishihara Y, Ishida K, et al. Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice. NPJ Aging Mech Dis. 2017;3:15.
   PubMed Web of Science ®Google Scholar
• Tang Z, Liang D, Cheng M, et al. Effects of Porphyromonas gingivalis and its underlying mechanisms on Alzheimer-like tau hyperphosphorylation in Sprague-Dawley rats. J Mol Neurosci. 2021 Jan;71(1):89–100.
   PubMedGoogle Scholar
• Kanagasingam S, Chukkapalli SS, Welbury R, et al. Porphyromonas gingivalis is a strong risk factor for Alzheimer’s disease. J Alzheimers Dis Rep. 2020 Dec 14;4(1):501–511.
   PubMedGoogle Scholar
• Lonn J, Ljunggren S, Klarstrom-Engstrom K, et al. Lipoprotein modifications by gingipains of Porphyromonas gingivalis. J Periodontal Res. 2018 Jun;53(3):403–413.
   PubMed Web of Science ®Google Scholar
• Raha D, Broce S, Arastu-Kapur S, et al. Gingipains identified in Alzheimer’s disease brains differentially fragment ApoE proteins. SSRN. 2021. 10.2139/ssrn.3838996.
   Google Scholar
• Munoz SS, Garner B, Ooi L. Understanding the role of ApoE fragments in Alzheimer’s disease. Neurochem Res. 2019 Jun;44(6):1297–1305.
   PubMed Web of Science ®Google Scholar
• Olsen I. Porphyromonas gingivalis-induced neuroinflammation in Alzheimer’s disease. Front Neurosci. 2021;15:691016.
   PubMed Web of Science ®Google Scholar
• Raha D, Broce S, Haditsch U, et al. COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients. Alzheimer’s & Dementia. 2020;16(S9):e040578.
   Google Scholar
• Kaba S, Lynch C, Raha D, et al. Clinical trials and aging: 11th conference clinical trials on Alzheimer’s disease, October 24-27, 2018, Barcelona, Spain. J Prev Alzheimer’s Dis. 2018;5:1–151.
   Google Scholar
• Detke MJ, Sabbagh MN. Top-line results from the GAIN trial: a phase 2/3 study of atuzaginstat in mild to moderate Alzheimer’s disease (CTAD 2021 Presentation): CTAD 2021 conference presentation; 2021 [ updated 2021 Nov 9-12; cited 2022 Apr 11]. Available from: https://ir.cortexyme.com/static-files/1cf9c299-a86c-490e-8342-fb1bb9efa5c2
   Google Scholar
• Cortexyme. Cortexyme announces clinical hold on atuzaginstat's investigational new drug application. South San Francisco (CA): Business Wire; 2022 Jul 22. Available from: https://www.cortexyme.com/cortexyme-announces-clinical-hold-on-atuzaginstats-investigational-new-drug-application/
   Google Scholar