Publications and Presentations
Pandey K, Duong D, Waybright L, Lizama B, Mecca A, van Dyck C, Grundman M, Blennow K, Zetterberg H, Caggiano AO, Seyfried N, Hamby ME Pharmacodynamic Effects of the S2R Modulator CT1812 in Alzheimer’s Disease (AD) Patients Observed in a Meta-analysis of CSF Proteomes from SPARC and SHINE Part A. Poster presented at: AD/PD™ 2023 International Conference on Alzheimer’s and Parkinson’s Diseases
Lizama BN, Kahle J, Catalano SM, Caggiano AO, Grundman M, Hamby ME. Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases. Int. J. Mol. Sci. 2023, 24(7), 6251
Pandey K, Waybright L, Duong DM, Malagise E, Blennow K, Zetterberg H, Mecca AP, van Dyck CH, Caggiano AO, Seyfried NT, Hamby ME (2022 August). CSF Proteomics Biomarker Analysis from the SPARC Clinical Trial: to Assess the Effect of the Sigma-2 Receptor (S2R) Modulator CT1812 in Alzheimer’s Disease Patients. Oral presentation at: 2022 Alzheimer’s Association’s International Conference (AAIC); San Diego, CA.
Malagise E, Keeling E, Knezovich N, Waybright L, Watto E, Caggiano AO, Ratnayaka A, Hamby ME (2022 May). Sigma-2 receptor modulators rescue POS trafficking deficits in RPE cell-based models of dry AMD. Poster presented at: 2022 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); Denver, CO.
Izzo NJ, LaBarbera KM, Yuede CM, Waybright L, Yurko R, Sheline YI, Edwards HM, Gardiner WD, Blennow K, Zetterberg H, Hanson AB, Davis CS, Guttendorf RJ, Schneider LS, DeKosky S, Caggiano AO, Grundman M, Catalano SM, Cirrito JR, Hamby ME (2022 March). Experimental Therapeutic CT1812 Demonstrates Target Engagement in a Phase 1b Clinical Trial to Measure Displacement of Aβ Oligomers Into CSF. Poster presented at: AD/PD™ 2022 International Conference on Alzheimer’s and Parkinson’s Diseases; Barcelona, Spain.
Seyfried N, Waybright L, Duong D, Malagise E, Pandey K, Williams C, Dammer E, Ping L, Blennow K, Zetterberg H, Lah J, Levey A, Ricciardi L, Caggiano AO, Hamby ME (March 2022). Proteomic Analysis of CSF in a Phase 2 Clinical Trial for AD to Identify Pharmacodynamic Biomarkers of the S2R Modulator CT1812. Poster presented at: AD/PD™ 2022 International Conference on Alzheimer’s and Parkinson’s Diseases; Barcelona, Spain.
Colom-Cadena M, Tulloch J, Jackson RJ, Catterson JH, Rose J, Davies C, Hooley M, Anton-Fernandez A, Dunnett S, Tempelaar R, Tzioras M, Izzo NJ, Catalano SM, Smith C, Spires-Jones TL. TMEM97 increases in synapses and is a potential synaptic Aβ binding partner in human Alzheimer’s disease. bioRxiv 2021.02.01.428238
LaBarbera KM, Limegrover C, Rehak C, Yurko R, Izzo NJ, Knezovich N, Watto E, Waybright L, Catalano. Modeling the mature CNS: A predictive screening platform for neurodegenerative disease drug discovery. J Neurosci Methods. 2021 Jul 1;358:109180.
Rishton GM, Look GC, Ni Z-J, Zhang J, Wang Y, Huang Y, Wu X, Izzo NJ, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, Catalano SM. Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer’s Disease. ACS Med Chem Lett. 2021 Aug 9;12(9):1389-1395.
Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, Waybright L, Look G, Rishton G, Safferstein H, Hamby ME, Williams C, Sadlek K, Edwards HM, Davis CS, Grundman M, Schneider LS, DeKosky ST, Chelsky D, Pike I, Henstridge C, Blennow K, Zetterberg H, LeVine H, Spires-Jones TL, Cirrito JR Catalano SM. Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer’s disease modification. Alzheimer’s Dement. 2021 Aug; 17(8):1365-1382
Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein. J Neurosci Res. 2021; 00: 1– 16.
Izzo NJ, Colom-Cadena M, Riad AA, Xu J, Singh M, Abate C, Cahill MA, Spires-Jones TL, Bowen WD, Mach RH, Catalano SM. Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease. 7(6) ENEURO .0317-20.2020 1–7
Limegrover, CS, LeVine, H, III, Izzo, NJ, Yurko, R, Mozzoni, K, Rehak, C, Sadlek, K, Safferstein, H and Catalano, SM. Alzheimer’s Protection Effect of A673T Mutation May Be Driven by Lower Aβ Oligomer Binding Affinity. J Neurochem. 2020; 00: 1–15
Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, Fillit H, Harrison JE, Schneider LS, Scheltens P, de Haan W, Grundman M, van Dyck CH, Izzo NJ, Catalano SM and the Synaptic Health Endpoints Working Group. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alz Res Therapy 12, 21 (2020)
Grundman M, Morgan R, Lickliterd JD, Schneider LS, DeKosky S, Izzo NJ, Guttendorf R, Higgin M, Pribyli J, Mozzoni J, Safferstein H, Catalano SM. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y). 2019 Jan 23; 5:20-26
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity PLoS One. 2014 Nov 12; 9(11):e111899
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits PLoS One. 2014 Nov 12; 9(11):e111898
Galvin JE, Tolea MI, Hamby ME, Grundman M, Caggiano AO. A Randomized, Double-blind, Placebo-controlled, Phase 2, Six-month Study to Evaluate the Safety, Tolerability and Exploratory Efficacy of CT1812 in Participants with Mild-to-Moderate Dementia with Lewy Bodies. Poster presented at: 2022 Clinical Trials on Alzheimer’s Disease Congress; San Francisco, CA.
Foundational Principles of Neuroscience:
- Takeuchi T, Duszkiewicz AJ, et al. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2; 369(1633)
- Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001 Nov 2;294(5544):1030-8
- Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973 Jul; 232(2):331-56.
- Ramón y Cajal S The structure and connexions of neurons (Lecture delivered December 12, 1906). In: (eds) Nobel Lectures, Physiology or Medicine 1901–1921. Elsevier Publishing Company, Amsterdam-London-New York
- Karch CM, Cruchaga C, et al. Alzheimer’s Disease Genetics: From the bench to the clinic. Neuron. 2014 Jul 2; 83(1): 11–26
- Tanzi, RE. The Genetics of Alzheimer Disease. Cold Spring Harb Perspect Med. 2012 Oct 1; 2(10)
- de Wilde MC, et al. Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement. 2016 Jun;12(6):633-44
- Scheff SW, et al. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007 May 1; 68(18):1501-8
- Scheff SW, et al. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2006 Oct; 27(10):1372-84
- DeKosky ST and Price DA. Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging. 2003 Dec; 24(8):1029-46
- Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002; 298:789–791
- Rössler M, et al. Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer’s disease. Acta Neuropathol. 2002 Apr; 103(4):363-9
- DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration. 1996 Dec; 5(4):417-21
- Lassmann H, Fischer P, Jellinger K. Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci. 1993 Sep 24;695:59-64
- Terry RD, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580
- DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Annals of Neurology. 1990 May; 27(5):457-64
- Esparza TJ, Gangolli M, et al. Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls. PLoSOne. 2018 Jul 6; 13(7)
- Brody DL, Jiang H, et al. Non-canonical soluble amyloid-beta aggregates and plaque buffering: controversies and future directions for target discovery in Alzheimer’s disease. Alzheimers Res Ther. 2017 Aug 17; 9(1):62
- van Maanen EM, van Steeg TJ, et al. Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool. J Pharmacol Exp Ther. 2016 Apr; 357(1):205-16
- Brinkmalm G, Hong W, et al. Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain. Brain. 2019 May 1;142(5):1441-1457
- Savioz A, Giannakopoulos P, et al. A Study of Aβ Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer’s Disease Compared to Aged Controls. Neurodegener Dis. 2016; 16(5-6):398-406
- Esparza TJ, Zhao H, et al. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol. 2013 Jan; 73(1):104-19
- Tomic JL, Pensalfini A, et al. Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis. 2009 Sep; 35(3):352-8
- Smith LM, Kostylev MA, et al. Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem. 2019 Apr 12; 294(15):6042-6053
- Zhao J, Li A, et al. Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluRin the Hippocampal CA1 Region. iScience. 2018 Aug 31; 6:138-150
- Smith LM, Strittmatter SM. Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity. Cold Spring Harb Perspect Med. 2017 May 1; 7(5)
- Cline EN, Bicca MA, et al. The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis. 2018; 64(s1):S567-S610
- Selkoe DJ, Hardy J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Molecular Medicine. 2016 Jun; 8(6):595-608
- Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014 May 21; 82(4):756-71
- Mucke L, Selkoe DJ. Neurotoxicity of Amyloid β-Protein: Synaptic and Network Dysfunction. Cold Spring Harb Perspect Med. 2012 Jul; 2(7):a006338
- Walsh DM, Klyubin I, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4; 416(6880):535-9
- Lambert MP, Barlow AK, et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998 May 26; 95(11):6448-53
- Alon A, Schmidt HR, et al. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165
- Riad A, Zeng C, et al. Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Sci Rep. 2018 Nov 15;8(1):16845
- Schindler SE, Li Y, et al; Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2019 May;15(5):655-665
- Dhiman K, Blennow K, et al. Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis. Cell Mol Life Sci. 2019 May;76(10):1833-1863
- Chen MK, Mecca AP, et al. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1; 75(10):1215-1224
- Mormino EC, Jagust WJ. A New Tool for Clinical Neuroscience-Synaptic Imaging. JAMA Neurol. 2018 Oct 1; 75(10):1181-1183
- Toledo JB, Arnold M, et al. Metabolic network failures in Alzheimer’s disease: A biochemical road map. Alzheimers Dement. 2017 Sep; 13(9):965-984
- Russell CL, Mitra V, et al. Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by MassSpectrometry Provides New Biomarker Candidates. J Alzheimers Dis. 2017; 55(1):303-313
- Öhrfelt A, Brinkmalm A, et al. The Pre-Synaptic Vesicle Protein Synaptotagmin is a Novel Biomarker for Alzheimer’s Disease. Alzheimer’s Research & Therapy. 2016; Oct 3; 8(1):41
- Janelidze S, Hertze J, et al. Cerebrospinal Fluid Neurogranin and YKL-40 as Biomarkers of Alzheimer’s Disease. Annals of Clinical and Translational Neurology. 2015 Nov 20; 3(1):12-20
AMD Rationale:
- Wang JH, Urrutia-Cabrera D, Mesa Mora S, Nguyen T, et al. Functional study of the AMD-associated gene TMEM97 in retinal pigmented epithelium using CRISPR interference. bioRxiv 2020 July 10 doi:10.1101/2020.07.10.198143
- Wang s, Wang x, Cheng y, et al. Autophagy Dysfunction, Cellular Senescence, and Abnormal Immune-Inflammatory Responses in AMD: From Mechanisms to Therapeutic Potential. Oxid Med Cell Longev. 2019; 2019: 3632169
- Mir SUR, Schwarze SR, Jin L, et al. Progesterone receptor membrane component 1/Sigma-2 receptor associates with MAP1LC3B and promotes autophagy. Autophagy, 9:10, 1566-1578
- Luibl V, Isas JM, Kayed R, et al. Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J Clin Invest. 2006; 116(2): 378-385
- Lynn SA, Keeling E, Munday R, et al. The complexities underlying age-related macular degeneration: could amyloid beta play an important role? Neural Regen Res. 2017; 12(4): 538-548
- Keeling E, Chatelet DS, Johnston DA, et al. Oxidative Stress and Dysfunctional Intracellular Traffic Linked to an Unhealthy Diet Results in Impaired Cargo Transport in the Retinal Pigment Epithelium (RPE). Mol Nutr Food Res. 2019; 63(15): e1800951
- Ahmed IS, Rohe HJ, Twist KE, Craven RJ. Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J Biol Chem. 2010; 285(32): 24775-24782
- Kabe Y, Handa H, Suematsu M. Function and structural regulation of the carbon monoxide (CO)-responsive membrane protein PGRMC1. J Clin Biochem Nutr. 2018; 63(1): 12-17.
- Riad A, Zeng C, Weng CC, et al. Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Sci Rep. 2018; 8(1):16845
- van Leeuwen EM, Emri E, Merle BMJ, et al. A new perspective on lipid research in age-related macular degeneration. Prog Retin Eye Res. 2018; 67:56-86
- Ahmed IS, Chamberlain C, Craven RJ. S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opin Drug Metab Toxicol. 2012; 8(3): 361-370.
- Sanchez-Pulido L, Ponting CP. TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Front Genet. 2014;5:439