As you may know, I co-founded Repair Biotechnologies, a company presently focused on developing an approach to rapidly reverse the cholesterol content of atherosclerotic lesions, a goal that is impossible to achieve using the existing panoply of treatments for atherosclerosis.
We use gene therapy techniques to provide cells with the ability to safely break down excess cholesterol, enabling the removal of pathological levels of intracellular cholesterol and localized deposits of extracellular cholesterol that characterize conditions such as atherosclerosis (in blood vessel walls) and NASH (in the liver). Atherosclerosis is an important consequence of aging: the structural weakness and narrowing in blood vessels caused by the growth of cholesterol-laden lesions is the cause of death for a quarter of humanity. Closer to half of humanity were cancer somehow removed from the human condition.
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The Foresight Institute runs salons these days, and publishes a range of interesting presentations from people in the biotechnology, molecular nanotechnology, and artificial general intelligence fields. Earlier this year, the Foresight Institute staff were kind enough to invite me to present on the work taking place at Repair Biotechnologies, and the understanding of atherosclerosis that informs that work.
I titled the presentation “Atherosclerosis, the As Yet Undefeated Monster” in part as a reaction to a certain type of conversation that recurs when talking to venture capitalists. Many biotech investors, and others too, seem to think that atherosclerosis is a solved problem, and therefore a poor choice of field in which to see a return by supporting the development of new approaches. Many of the best-selling small molecule drugs are statins that have been deployed for decades to treat atherosclerosis by lowering LDL cholesterol in the bloodstream. Physicians reflexively prescribe statins to older individuals. Everyday people obsess about their blood cholesterol levels. New LDL cholesterol lowering drugs that employ modern technologies such as monoclonal antibodies and siRNA are being approved for use on an ongoing basis.
Yet in this environment of decades of ever more attention given to the reduction of LDL cholesterol levels in the bloodstream, atherosclerosis still kills a quarter of humanity. Atherosclerosis is very far removed from being a solved problem! There is an enormous unmet need and ongoing mortality, on a par with the global burden of cancer.
LDL cholesterol reduction as a basis for therapy can lower late life mortality by 20% at most, with many large, robust clinical trials failing to obtain even that degree of benefit. It just isn't the right mechanism if the goal to produce a cure. It doesn't matter how efficiently a therapy reduces LDL cholesterol in the bloodstream, that 20% mortality reduction appears to be a ceiling. PCSK9 inhibitors do no better than statins when it comes to lowered mortality following control of LDL cholesterol, despite being a much more modern and capable technology. I feel that perhaps the research and development community has been encouraged in its near monomaniacal fixation on lowering LDL cholesterol by the discovery of human gene variants (in PCSK9, ANGPTL3, and so forth) that result in lower LDL cholesterol and up to 50% lower cardiovascular mortality. But that result is obtained due to a full lifetime of lowered LDL cholesterol. Therapies built on those discoveries cannot match that outcome.
Atherosclerotic lesions grow over time at a pace that is influenced by LDL cholesterol levels, by the pace at which cholesterol arrives from the bloodstream to a lesion. Reducing that pace via LDL cholesterol lowering therapy cannot reverse established lesions, or even stop them from further growth and eventual rupture, however. Once a lesion is established, the more important mechanism is the dysfunction of the macrophage cells responsible for clearing cholesterol from blood vessel walls. Those cells are overwhelmed, become inflammatory, attract more macrophages, and die, adding their mass to the lesion. The lesion becomes a macrophage graveyard.
To actually reverse atherosclerotic lesions, to actually produce a treatment that could legitimately be called a cure for atherosclerosis, one needs to protect the function of macrophages in the hostile, inflammatory, cholesterol-laden atherosclerotic plaques. If macrophages can be made invulnerable to excess cholesterol, and other harms such as oxidized LDL particles, then given enough time they will do their jobs and repair the blood vessel wall. That is our goal at Repair Biotechnologies, to make a real and meaningful inroad towards that goal.
Atherosclerosis: The As Yet Undefeated Monster
Source: Fight Aging!