Our Cholesterol Degrading Platform by Repair Biotechnologies
Our Cholesterol Degrading Platform
Where we come in
Human cells cannot degrade cholesterol, leading to abnormal accumulation of excess cholesterol in vital organs and the onset and progression of several chronic and orphan diseases. Repair Biotechnologies’ Cholesterol Degrading Platform (CDP) therapy solves this by providing specific cells with the ability to degrade excess or modified cholesterol.
What we aim to change
Atherosclerosis is the build-up of cholesterol-based plaques that eventually protrude into the lumen of arteries and block blood flow. This is the most common contribution to heart disease, stroke, and death. Plaque burden is a reliable predictor of cardiovascular events and poor outcomes.
To date no therapy, or even intensive combination of therapies, can reliably and rapidly reduce plaque size and overall plaque burden to a sizable degree in more than a small fraction of treated patients. The few impressive results do not replicate in the broader population.
What sets CDP apart
By safely breaking down excess cholesterol, we believe that CDP can repair the failure of reverse cholesterol transport that is at the heart of atherogenesis. Rather than accumulating to make macrophages dysfunctional, excess cholesterol will instead be catabolized.
Currently, medical treatments for atherosclerosis alter aspects of normal lipoprotein metabolism to slow the accumulation of lipoproteins (principally LDLs) in the vasculature. A large number of clinical trials indicate that statins, which are inhibitors of cholesterol production, reduce cardiovascular events (e.g. heart attacks and strokes) by about 25%. While this represents a remarkable achievement, a 25% reduction means that 75% of patients with cardiovascular disease still suffer cardiovascular events.
Shrinking of existing atherosclerotic plaque burden is strongly correlated with reduced incidence of cardiovascular events. Statin treatment does not usually significantly reduce plaque, and even in the cases where it can, statins must be aggressively administered to achieve LDL <70 mg/dL and HDL >60mg/dL. Such regimens come with increased risk of weight gain, worsening of diabetes, muscle aches and pain, kidney and liver complications and brain hemorrhage. Furthermore, pregnant women cannot use statins because of the known deleterious effects on fetal development. Finally, the degree of shrinkage of established plaque is modest at best, less than 10% in most clinical trials.
Current therapies thus largely act to slow the progression of existing atheromas only, and these structures remain within the walls of affected vascular structures to cause potentially lethal complications.
A single treatment of Repair Biotechnologies’ early, unoptimized CDP therapy, delivered as an adeno-associated virus (AAV) gene therapy vector, reduced atherosclerotic plaque lipids by 48% in mice. The image shows stained sections of the aortic root from the control and treatment groups, in which areas of plaque show up in red. In this experiment, atherosclerosis-prone mice were placed on a high-fat diet and angiotensin II for 4 weeks. The treatment group was administered CDP therapy, and at 4 weeks post-injections, mice were euthanized.
Various organs including the heart and aortic tree were removed and processed for histology. Throughout the experimental protocol, mice in all groups were mobile, looked healthy and did not display any weight loss or signs of distress. Liver AST and ALT levels and their ratios remained unchanged between control-treated and CDP-treated groups.
The present optimized form of CDP therapy moving into clinical development makes use of lipid nanoparticle (LNP) delivery of messenger RNA (mRNA). In the LDLR-null mouse model of homozygous familial hypercholesterolemia, a rare condition exhibiting greatly accelerated development of atherosclerosis, six weeks of treatment with this LNP-mRNA CDP therapy produces a 17% reduction in aortic plaque cross-sectional area and consequent sizable improvement in cardiovascular function, as illustrated by improved treadmill performance.
Unlike current standards of care such as statins and the more modern PCSK9 inhibitors, both of which aim to reduce circulating levels of LDL-cholesterol, and have a minimal impact on atherosclerotic plaque size and burden, treatment with CDP therapies resulted in a sizable reduction in plaque burden in the aortic roots of atherosclerosis-prone mice.
