Repair Biotechnologies, Inc. (“Repair”), based in Upstate New York, develops gene therapies capable of reversing atherosclerosis in animal models by targeting a previously undruggable mechanism.
Unlike many of the molecules vital to cell structure and function, cells do not create and destroy cholesterol locally. Manufacture of cholesterol is an energetically expensive process that takes place largely in the liver, with some cholesterol additionally obtained from the diet. Cholesterol is transported around the body to where it is needed via a complex system of hand-offs and carrier molecules. This system inevitably breaks down with advancing age, as well as in obesity, leading to localized excesses of cholesterol that overwhelm the ability of cells to safely store cholesterol in an esterified form or manage its uptake. This produces harm by allowing toxic levels of excess free, non-esterified cholesterol to exist within cells, leading to cell dysfunction and cell death.
This excess free cholesterol is an important driving mechanism in atherosclerosis, including the accelerated atherosclerosis of familial hypercholesterolemia, resulting from genetic mutations affecting cholesterol trafficking. The cholesterol-rich plaques of atherosclerosis build up in blood vessel walls, eventually becoming unstable and rupturing to produce heart attacks and strokes, the greatest causes of human mortality. Free cholesterol also drives metabolic-dysfunction associated steatohepatitis (MASH), and is strongly implicated in a variety of neurodegenerative conditions, as well as other obesity-associated diseases.
Intracellular free cholesterol is, unfortunately, an undruggable target for small molecule therapeutics. There is no cholesterol degradation process operating in cells, so no possibility of a small molecule to upregulate that non-existent process. Conversely, any small molecule capable of binding and sequestering free cholesterol in large enough amounts to make a difference to atherosclerotic plaque or a fatty liver would also kill cells by attacking the cholesterol present in cell membranes.
Instead, Repair Biotechnologies has developed a fusion protein capable of operating within cells to selectively and safely break down only excess intracellular free cholesterol. Delivered as a gene therapy using lipid nanoparticles (LNP) and messenger RNA (mRNA), this treatment rapidly and dramatically clears free cholesterol, and, as a consequence, produces equally rapid and dramatic reductions in plaque lipids and plaque size in mouse models of atherosclerosis, stabilizing unstable plaques and improving the health and activity of the animals.
The fatty and often unstable plaques of atherosclerosis are largely irreversible under the present standard of care. Intensive therapies in large clinical trials have produced perhaps a 1% shrinking of plaque over very long periods of intensive treatment. By targeting intracellular free cholesterol, never before attempted, Repair Biotechnologies has now demonstrated much larger reductions in plaque lipids and plaque size in mice in as little as six weeks of therapy.
Repair Biotechnologies is presently preparing for and conducting pre-IND meetings for indications including MASH, atherosclerosis, and familial hypercholesterolemia. The company aims to bring an end to the vast majority of cardiovascular mortality with its first-in-class and disease modifying approach that specifically targets intracellular free cholesterol as one of the most important mechanisms underlying the development of atherosclerosis and cardiometabolic disease in later life.