Therapeutics

CS6253

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Overview

Name: CS6253
Synonyms: Cogpep™, CS-6253
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Artery Therapeutics, Inc.

Background

This agonist peptide increases the activity of the adenosine triphosphate-binding cassette transporter A1 (ABCA1), which regulates cholesterol efflux from cells. ABCA1 transfers lipids to ApoE, and thus facilitates clearance of amyloid peptides from the brain. Loss-of-function variants in the ABCA1 gene are associated with low plasma levels of ApoE, and a higher risk of Alzheimer’s disease (Holstege et al., 2022; Nordestgaard et al., 2015).

Designed to mimic sequences at the carboxy terminus of ApoE, CS96253 was shown to enhance ABCA1-mediated lipid efflux from cells and formation of HDL particles in vitro (Hafiane et al., 2015; Hafiane et al., 2019). This peptide was initially pursued for its potential to improve or prevent cardiovascular disease.

However, in mice expressing the human AD risk gene ApoE4, CS6253 was reported to reverse hypo-lipidation of E4, slow Aβ accumulation and tau hyperphosphorylation in neurons, and improve synaptic and cognitive function (Boehm-Cagan et al., 2016). In the same mice, it restored blood lipoproteins to normal levels, and countered the ApoE4-induced lysosomal degradation of ABCA1 (Boehm-Cagan et al., 2016; Rawat et al., 2019). Intravenous injection of CS6253 in monkeys transiently increased plasma ApoE and Aβ42/40 (Noveir et al., 2022).

In other models, CS62523 was neuroprotective in fruit flies expressing a human ApoE4 gene (Moulton et al., 2021). It induced insulin secretion and improved glucose tolerance in mice with diet-induced obesity (Azhar et al., 2019), and reduced disability in a mouse model of multiple sclerosis (Itoh et al., 2018).

Findings

A Phase 1 safety trial is slated to begin in September 2023. It will enroll up to 64 healthy adults in five single-ascending-dose cohorts from 1 to 10 mg/kg, and two or more multiple dose groups. In the multiple dose part of the study, each cohort of eight will have at least four ApoE4 carriers. The drug is administered by intravenous injection. Primary endpoints are safety, and plasma and CSF pharmacokinetics. The trial, funded by the National Institutes of Health and the Alzheimer’s Association, is expected to last one year.

For details on this trial, see clinicaltrials.gov.

Last Updated: 21 Sep 2023

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References

Paper Citations

  1. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
  2. Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease. Alzheimers Dement. 2015 Jun 13; PubMed.
  3. Hafiane A, Bielicki JK, Johansson JO, Genest J. Novel Apo E-Derived ABCA1 Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces Formation of preβ-1 HDL In Vitro. PLoS One. 2015;10(7):e0131997. Epub 2015 Jul 24 PubMed.
  4. Hafiane A, Johansson JO, Genest J. ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux-Dependent Mechanism. Can J Cardiol. 2019 Jun;35(6):770-781. Epub 2019 Feb 27 PubMed.
  5. Boehm-Cagan A, Bar R, Liraz O, Bielicki JK, Johansson JO, Michaelson DM. ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. J Alzheimers Dis. 2016 Oct 4;54(3):1219-1233. PubMed.
  6. Boehm-Cagan A, Bar R, Harats D, Shaish A, Levkovitz H, Bielicki JK, Johansson JO, Michaelson DM. Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins. PLoS One. 2016;11(11):e0166195. Epub 2016 Nov 8 PubMed.
  7. Rawat V, Wang S, Sima J, Bar R, Liraz O, Gundimeda U, Parekh T, Chan J, Johansson JO, Tang C, Chui HC, Harrington MG, Michaelson DM, Yassine HN. ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes. J Neurosci. 2019 Nov 27;39(48):9611-9622. Epub 2019 Oct 22 PubMed.
  8. Noveir SD, Kerman BE, Xian H, Meuret C, Smadi S, Martinez AE, Johansson J, Zetterberg H, Parks BA, Kuklenyik Z, Mack WJ, Johansson JO, Yassine HN. Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys. Alzheimers Res Ther. 2022 Jun 24;14(1):87. PubMed.
  9. Moulton MJ, Barish S, Ralhan I, Chang J, Goodman LD, Harland JG, Marcogliese PC, Johansson JO, Ioannou MS, Bellen HJ. Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer's disease-associated genes. Proc Natl Acad Sci U S A. 2021 Dec 28;118(52) PubMed.
  10. Azhar S, Bittner S, Hu J, Shen WJ, Cortez Y, Hao X, Han L, Lagerstedt JO, Kraemer FB, Johansson JO. Novel ABCA1 peptide agonists with antidiabetic action. Mol Cell Endocrinol. 2019 Jan 15;480:1-11. Epub 2018 Oct 2 PubMed.
  11. Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A, Ao Y, Farkhondeh V, Johnsonbaugh H, Burda J, Sofroniew MV, Voskuhl RR. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E302-E309. Epub 2017 Dec 26 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Suidan GL, Ramaswamy G. Targeting Apolipoprotein E for Alzheimer's Disease: An Industry Perspective. Int J Mol Sci. 2019 May 1;20(9) PubMed.
  2. Hafiane A, Johansson JO, Genest J. ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux-Dependent Mechanism. Can J Cardiol. 2019 Jun;35(6):770-781. Epub 2019 Feb 27 PubMed.
  3. Bielicki JK. ABCA1 agonist peptides for the treatment of disease. Curr Opin Lipidol. 2016 Feb;27(1):40-6. PubMed.