‘We’re seeing profound reversal of a number of conditions’

Repair Bio is harnessing gene therapy’s potential to clear excess cholesterol with a platform that could reshape cardiovascular treatment.

Repair Biotechnologies is developing a novel approach to cholesterol management with its Cholesterol Degrading Platform (CDP); this innovative approach moves beyond conventional cholesterol-lowering strategies, aiming instead to degrade cholesterol at the cellular level. 

The Syracuse, New York-based biotech is using unique lipid nanoparticle (LNP)-messenger RNA (mRNA) therapies designed to address the root causes of conditions stemming from localized cholesterol accumulation, setting a new standard in therapeutic interventions.

Unlike traditional methods that merely reduce LDL-cholesterol levels in the bloodstream, Repair Bio’s strategy targets the intracellular free cholesterol that is toxic to cells and a contributing factor in a variety of diseases. This approach not only promises to mitigate atherosclerosis but also shows potential in treating metabolic dysfunction-associated steatohepatitis (MASH), as evidenced by promising results in preclinical mouse models.

Longevity.Technology: Atherosclerosis, marked by the buildup of arterial plaque, significantly impedes blood flow and is a major contributor to cardiovascular disease (CVD) – the leading cause of death worldwide. To address this pressing health burden, scientists at Repair Bio have developed a novel LNP-mRNA therapy, and in recent experiments, atherosclerotic mouse models treated with this therapy over a six-week period demonstrated promising results. It is an innovative approach that not only holds potential for mitigating atherosclerosis but also offers a pathway to reducing the global burden of CVD, ultimately saving lives and improving health outcomes. 

The viability of this approach was further underscored when Repair Bio recently received favorable pre-IND feedback from the FDA, marking a significant milestone as the company prepares for clinical trials. We sat down with Reason, the Founder and CEO of Repair Bio, to find out more about the platform, upcoming clinical trials and tackling the Goldilocks problem in delivery systems.

Reason on…

The nature of cholesterol

Most people understand that as you go through life, you are supposed to have low blood cholesterol. Cholesterol is bad in the sense that if you exhibit raised LDL cholesterol in your blood, then you are not in a good position. But the cholesterol we’re interested in occurs at the point at which the transport of cholesterol in your body becomes disrupted either by aging or obesity, producing our target of localized excesses of cholesterol. The important thing to remember here is that even though cholesterol is vital, unmodified free cholesterol is toxic. Cholesterol is made safe by cells in a variety of ways, but cells have only a limited capacity to deal with any excess of it. If you have too much cholesterol in one location, that excess will generate free cholesterol, which becomes toxic when inside cells. Those cells begin to die if there’s enough of this free cholesterol, and well before that point, they will begin to become dysfunctional in many ways. An example of this is atherosclerosis, wherein the localized excess exists in a small region of your blood vessels, and everything nearby starts falling apart. Eventually, you suffer a stroke or a heart attack, and you die because the atherosclerotic plaque ruptured. The other important example is the liver, the center of your cholesterol metabolism. It’s where most cholesterol is created and then sent out into circulation – but in the case of fatty liver, in obesity and in aging, you simply have too much cholesterol. 

The liver is influential on the body in many ways, and if excessive cholesterol is stuck in the liver, becoming free cholesterol to some degree, then your liver suffers pathology. This appears to drive a number of conditions, but that was hard to prove until we introduced our approach to specifically and deliberately break down and remove only the excess free cholesterol. Given that capability, suddenly we can demonstrate profound reversal of a number of conditions, age-related and otherwise – and that is the fundamental basis for our technology. 

The necessity of gene therapy

Our platform uses gene therapy because gene therapy is the only way to get at the free cholesterol that’s inside cells – one must use some form of protein machinery that goes in and dismantles the cholesterol. Additionally, cholesterol is unlike many molecules in the body. It’s not made or broken down locally, rather you ingest it or it’s made in the liver, and then off it goes into circulation. Cells take it up as they need it, and when they don’t need it, they throw it back into circulation. This is a complicated system, and, like all complicated systems, it breaks down with age. Because there is no destroy cholesterol function, you can’t find a small molecule to manipulate that missing destroy cholesterol function. You can’t ‘small molecule’ your way into manipulating these masses of free cholesterol that are there, and the body can’t remove them on its own. So, one needs some sort of protein machinery and thus have to be making a gene therapy to supply that machinery. 

Gene therapy delivery mechanisms are a Goldilocks problem: some of them are too hot, some of them are too cold, some of them don’t last long enough, some of them last too long, and you’re picking the most optimal way forward. We found a very effective way forward in lipid nanoparticle delivery of messenger RNA that produces a short-term effect. It’s very like a small molecule drug in the way it behaves. You inject it, it goes somewhere, it produces your fusion protein for a few days, and then it’s gone. The only thing it leaves behind is the work that it did to reduce the pathology.  

Next steps

We’re hoping to conduct our IND in a fairly straightforward manner, and we’ll be in the clinic in early 2026. At that point, it is a first-in-human. Of course, there is some risk; you can never be sure as to how your technology is going to perform until you put it into people, so it’s an exciting time for us, but also nerve-wracking. We have a tremendous number of animal studies that have all performed wonderfully, but still, you have to jump through the hoop and see what happens in humans. 

Our first-in-human safety study will be evaluating dose-limiting toxicities, then we’ll move on from there to a focus on efficacy.  

In terms of commercial strategy, we plan to take the platform forward ourselves. As a biotech, you have to make sure that you can show value to potential partners by getting as far as you can on your own. At the point where we have clear human data that shows efficacy, that’s when we’ll be looking for partners to help us scale up and reach larger markets, however. The initial focus is always on proving the technology in humans, getting that data that shows it works, and then using that to attract the right partners to help take it further.