More Details on Cyclarity's Approach to Clearing 7-Ketocholesterol

This recent article from the SENS Research Foundation discusses calcium chelation and, separately, the tailored cyclodextrin molecules developed by Cyclarity to sequester 7-ketocholesterol. This altered form of cholesterol is toxic to cells, and may provide a significant contribution to a range of age-related conditions, including atherosclerosis. Cyclarity will be conducting initial human trials in the near future. Since the best way to determine exactly how important 7-ketocholesterol is in the context of atherosclerosis in humans is to remove it, it will be interesting to see how this goes. It is vital to progress that more programs of this nature make it to human trials, rather than becoming bogged down in academic questions over ways to determine the likely degree of efficacy in advance of clinical development.

Cyclarity's UDP-003 is a small molecule LysoSENS therapy that directly removes damaged cholesterol products that turn macrophages into foam cells and thus drive atherosclerosis. Researchers set out to design a molecular precision tool that would remove 7-ketocholesterol (7KC) selectively while leaving normal physiological cholesterol untouched. Using a combination of experimentation with existing cyclodextrins, trial-and-error virtual experiments in existing molecular modeling software, and eventually a new VR molecular modeling and design system, Cyclarity constructed a novel cyclodextrin dimer in virtual space and tested it in silico against native and oxidized cholesterol before testing it in actual lab conditions - and then back again to the virtual system in an iterative optimization cycle.

This dimer is comprised of two different cyclodextrins, one of them "scoop-like" and the other a "gripper" complex, linked together in a configuration where the two can cooperate to create a binding cavity. It's a bit like a reusable coffee pod or a shaker cup for protein shakes, with a chamber to take in the desired material and then a sealable cap to hold the contents in place. This dual structure allows UDP-003 to first capture 7KC and then surround it, holding on to it with extremely high affinity. Trapped in the UDP-003 core, 7KC can't interact or react with anything else in the body, allowing UDP-003 to passively carry it out of the cell, through the circulation, and harmlessly out of the body via excretion.

In experimental systems, UDP-003 sucks very high amounts of 7KC from cultured cells and blood cells, as well as from surgically captured atherosclerotic plaque, with no corresponding effect on free unmodified cholesterol in blood. A useful safety test is to see if a cyclodextrin will extract cholesterol out of the membranes of red blood cells, causing them to lyse; on such tests, UDP-003 has extremely little hemolytic activity.

In 2021, the UK's Medicines and Healthcare products Regulatory Agency (MHRA - their equivalent of FDA) awarded Cyclarity an Innovation Passport under its Innovative Licensing and Access Pathway (ILAP), which is a new program designed to help shepherd truly innovative therapies more quickly through the regulatory process by giving awardees early and ongoing contact and feedback with the regulators. Thanks to this and a solid scientific foundation, UDP-003 trials are coming up fast in the UK. As of this writing (late winter of 2023), Cyclarity is finishing up its animal safety data and getting ready to produce enough UPD-003 at pharmaceutical grade to run their first human trial. While only a safety trial, it will be a critical first-in-human test of the new molecule.



does anyone know if 7KC resides inside or outside the lysosome?

Posted by: erasmus at April 19th, 2023 3:51 PM
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