Fight Aging!

As some of you may know, I co-founded Repair Biotechnologies with Bill Cherman. The company is presently on the development of a gene therapy approach now demonstrated to rapidly reverse atherosclerosis in mice, the condition in which fatty plaques grow to narrow blood vessels and weaken blood vessel walls. One of the possible approaches to treating aging as a medical condition is to take the list of causes of human mortality, start at the top, and work down. Atherosclerosis is the single largest cause of death in our species, through the rupture of unstable atherosclerotic plaque leading to heart attack or stroke. The burden of established plaque correlates with mortality risk, but repeatable, sizable reversal of plaque in patients cannot be achieved by the current approaches to treatment that are focused on lifestyle factors and LDL-cholesterol level in the bloodstream.

To date, we have used our Cholesterol Degrading Platform (CDP) to demonstrate rapid and profound reversal of disease in mouse models of (a) metabolic dysfunction-associated steatohepatitis (MASH), a progression of fatty liver towards liver failure that is characterized by fibrosis and loss of liver function, (b) atherosclerosis, the buildup of fatty plaques in blood vessel walls, leading to cardiovascular disease and stroke, and (c) homozygous familial hypercholesterolemia (HoFH), an inherited condition involving loss-of-function mutations in low-density lipoprotein receptors (LDLR) that causes high blood cholesterol and greatly accelerated atherosclerosis.

These three conditions are characterized by being largely irreversible under the present standards of care. While slowing the progression of disease is sometimes possible, few patients have been shown to achieve any meaningful reversal of established liver fibrosis or arterial atherosclerotic plaque, and the methods used to treat those patients are not consistently effective in other patients.

In each case, 6 to 8 weeks of once-weekly injections of CDP therapy produced sizable improvements in blood chemistry, including reductions in alanine aminotransferase (ALT), a measure of liver cell death and stress, and in histological assessments of disease. In MASH model mice, a 52% reduction in liver fibrosis was observed versus untreated controls. In the ApoE-knockout mouse model of atherosclerosis, plaque lipids were reduced by 19% while plaque collagen increased by 23% versus controls, a dramatic stabilization of unstable plaques at risk of rupture. In the LDLR-knockout mouse model of HoFH, plaque cross-sectional area decreased by 17% and mouse treadmill performance improved by 60% versus controls, a considerable improvement in cardiovascular function.

To compare this with other present efforts, the drug, resmetirom (Madrigal Pharmaceuticals), recently approved by the FDA for the treatment of MASH, has no effect on fibrosis in mice over 8 weeks of treatment. In the MAESTRO human trial in patients with comparatively mild MASH, the treated groups saw only a 25% reduction in fibrosis compared to 14% in the placebo group after 52 weeks of treatment. In the case of atherosclerosis, large clinical trials have shown that long-term treatment with statins or other low-density lipoprotein (LDL)-lowering technologies such as PCSK9 inhibitors fails to produce a reduction in atherosclerotic plaque volume of more than a few percentage points. Our CDP therapy far outperforms these approaches to treatment.

Perhaps the most interesting outcome is that we have demonstrated that a localized excess of free cholesterol is indeed a major factor in many conditions, age-related and obesity-related. It had been theorized that this was the case for liver diseases such as MASH, but lacking a technology that selectively cleared only free cholesterol, this had to remain only a compelling theory. Armed with that selective clearance technology, our results have now convincingly demonstrated that free cholesterol toxicity is a major, important target for many conditions.

Link: https://www.lifespan.io/news/new-gene-therapy-reverses-atherosclerosis-in-mice/