A quarter of humanity dies from heart attack and stroke, caused when an atherosclerotic plaque ruptures to create fragments that block an important blood vessel. Everyone develops atherosclerotic plaque to some degree with advancing age. Cholesterol is manufactured in the liver and transported in the bloodstream attached to forms of low density lipoprotein (LDL) particles. Excess cholesterol is ingested by macrophages and then attached to high density lipoprotein (HDL) particles for transport back to the liver and reuse. This is a complex system of many moving parts and regulators and sensors, and like all complex systems, it runs awry with the damage of aging or obesity. In particular, excess deposition of cholesterol into blood vessel walls starts to overwhelm the ability of macrophages to clean it up, and a fatty plaque begins to form to narrow and weaken that blood vessel.
That is a very high level description, but dive deeper and there is increasing complexity in the details. Other factors are involved, such as the state of chronic inflammation, making macrophages less able to undertake repair activities. Or the presence of oxidized cholesterols or oxidized LDL particles that are more disruptive than cholesterol and LDL, molecule for molecule. Or other mechanisms that can hamper macrophages, increase inflammatory reactions in blood vessels, or otherwise alter cholesterol transport for the worse, from the effects of hypertension on cells in blood vessel walls to the pro-inflammatory signaling of senescent cells to raised levels of lipoprotein (a).
To date, most approaches to the treatment of atherosclerosis have focused on lowering LDL cholesterol levels in the bloodstream. Unfortunately this only (b) slows plaque growth, (b) very slowly, over years, makes plaques a little less likely to rupture by reducing their lipid content. Lowering LDL cholesterol in the bloodstream cannot reliably or rapidly regress atherosclerotic plaque, and so a quarter of humanity continues to die from the consequences of having atherosclerotic plaque. There are a great many other targets that research and development programs might choose as a basis for therapy, however. The challenge, as ever in the matter of everything to do with aging, is that the only good way to find out whether a given approach works well is to try it. Determining just how important one mechanism is versus all the others can only really be determined by fixing that one problem in isolation and observing the results.
So far, all of the well-funded alternative approaches to lowering LDL cholesterol in the bloodstream have failed to demonstrate the ability to reliably and rapidly regress atherosclerotic plaque. Bitterroot Bio's CD47-based approach only slows plaque growth. The same goes for the Silence Therapeutics approach to lowering circulating lipoprotein (a). And so forth. Of the less well funded approaches that have made it out of the laboratory and into preclinical development in biotech companies, so far as I am aware only Repair Biotechnologies and VasoRx have mouse data showing significant plaque regression.
(To be clear, every boutique cardiovascular physician can roll out a few patients with amazing plaque reduction from whatever their special combination of lifestyle interventions, LDL-lowering therapies, and other treatments happens to be. The problem is that any degree of regression of atherosclerotic plaque isn't the reliable outcome for any of these approaches. The average for plaque regression is close to zero. New technologies, new approaches are needed).
Cyclarity Therapeutics is an interesting case. Like Repair Biotechnologies, this company emerged from the SENS community, though unlike Repair Biotechnologies the scientific program giving rise to the company was developed at the SENS Research Foundation. The company uses carefully designed cyclodextrins to sequester and clear 7-ketocholesterol, a toxic altered form of cholesterol that is suggested to be important in driving atherosclerosis by incapacitating the macrophages attempting to repair atherosclerotic plaque. There is no animal model that exhibits a human-like level of 7-ketocholesterol, however. It would be very costly in time and funding to produce and validate such a model, so the Cyclarity leadership chose to move directly into humans without the usual preclinical animal data to show effects on plaque - and fortunately found investors willing to fund that program. We can hope that clearing 7-ketocholesterol will be a way to reliably regress atherosclerotic plaque! Yet it may prove to be another way to only slow the growth of plaque. The only way to find out is to try it and see.
Cyclarity Therapeutics Secures Approval for First-in-Human Clinical Trial
Cyclarity Therapeutics is pleased to announce regulatory approval to begin its first-in-human clinical trial. The trial will be conducted at CMAX, one of Australia's leading clinical research centers, in partnership with Monash University. This effort will be led by Dr. Stephen Nicholls of the Victorian Heart Institute (VHI), a distinguished leader in cardiovascular medicine. In addition to a traditional single (SAD) and multiple ascending dose (MAD) phase 1 trial, the authorization includes an allowance to enroll 12 patients with Acute Coronary Syndrome (ACS) to assess the safety of UDP-003 in individuals with plaque buildup, as well as to explore anecdotal evidence of efficacy. This represents a critical first step in evaluating the potential impact of our therapy in a population with high unmet need.
Cyclarity Therapeutics: Our Science
Cyclarity aims to deliver simple and affordable therapies for cardiovascular disease and other chronic diseases of aging. Cyclarity's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function. Our Lead Product: UDP-003 is a first-in-class drug; a specially engineered cyclodextrin which will target and remove toxic oxidized cholesterol, a key driver of atherosclerosis, neurodegenerative diseases, and other chronic diseases. UDP-003 is designed to restore the cardiovascular self-repair function and reduce arterial plaque.
View the full article at FightAging
