Will cholesterol-busting gene therapy become the ‘true inheritor’ of statins?

Following compelling preclinical results, Repair Bio’s cholesterol-degrading platform is gearing up for clinical trials in atherosclerosis.

Following the recent revelation that its cholesterol-degrading technology rapidly reverses the progression of atherosclerosis in multiple preclinical models, gene therapy company Repair Biotechnologies is now moving forward with plans to move into human trials. Having received favorable initial feedback, the New York-based biotech is raising funding as it prepares for further discussions with the US FDA as it aims to advance its therapies into clinical trials for the treatment of atherosclerosis in humans.

Longevity.Technology: Atherosclerosis, a condition characterized by the buildup of plaque in arteries, contributes significantly to heart disease, stroke and death. While most treatment approaches typically focus on reducing LDL-cholesterol levels in the bloodstream, Repair Bio’s lipid nanoparticle (LNP)-messenger RNA (mRNA) therapy targets something called “intracellular free cholesterol” – an approach it claims holds great potential to reverse the condition and significantly reduce the risk of cardiovascular events. To learn more, we caught up with the company’s founder and CEO, Reason.

One of the big challenges with cholesterol, says Reason, is that once it’s in your body, it’s pretty much there to stay.

Reason is Repair Bio‘s founder and CEO.

“Cholesterol is only created in limited number of places in the body, primarily the liver, and dietary cholesterol contributes only a smaller amount on top of that,” he says. “After it’s created in your body, or ingested, then it gets shipped around to where it is needed – and wherever it’s carted around the body, or stashed, or stored, it’s usually modified in some way, to make it safe.”

Free cholesterol is toxic

Our body’s ability to deal with cholesterol safely is limited by the capacity of our cells to alter cholesterol, such as by esterifying the molecule, or attaching it to transport particles like LDL or HDL.

“The passage of cholesterol around the body while attached to transport particles is a dynamic equilibrium,” says Reason. “Perturbations of that equilibrium, whether random happenstance, fluctuations in your diet, or the damage of aging will tend to create localized pockets of excessive cholesterol.”

“As a rule, our cells cannot break down cholesterol, so they must try to deal with the excess by putting it back into circulation to send it off to where it’s meant to go – or at least esterify it into a safe form for storage inside cells as lipid droplets,” he adds. “These processes are easily overwhelmed, however, and the result is localized excesses of unmodified or “free” cholesterol – and it’s important to remember that cholesterol on its own, this free cholesterol, is toxic.”

Add something like obesity into the mix, and the cholesterol equilibrium is shifted even further out of balance.

“In obesity, an individual has so much cholesterol everywhere that the body runs out of places to put it, and every tissue will be overwhelmed,” says Reason. “One of the main reasons why obese people exhibit a greater burden of chronic disease is because they have much more toxic free cholesterol to disrupt cell behavior. They can’t get rid of it, they can’t put it anywhere, and it’s overwhelming the system.”

Aging plays its part

Aging is also a significant factor, with older people experiencing similar, if more subtle, effects to those seen in obesity.

“Aging is the bane of all complex systems in the body, cholesterol transport included – again, the result is localized excesses of cholesterol, not only in places like the arteries and blood vessels, but also in the liver,” says Reason. “Fatty liver disease is a growing issue in much of the world. This system is breaking down – the normal balance of cholesterol is disrupted, and a growing fraction of cholesterol is free. That free cholesterol disrupts normal tissue function.”

“Aging is damage, so if your intervention is not repairing some form of damage, or reducing the accumulation of some pathological substance, then you’re probably not doing as much good as you could be,” adds Reason. “In this case, the pathological substance is cholesterol generally, when present in localized excess, but more specifically, the bad part of that is the free cholesterol.”

A cholesterol degrading platform

Our body’s inability to deal with this excess accumulation of free cholesterol is the foundation of Repair Bio’s cholesterol degrading platform technology. The company licensed the technology in 2018, which essentially makes cells resilient to excess cholesterol, and thus reduces much of the dysfunction that leads to atherosclerotic damage.

“When we first came across the technology that we now call our cholesterol degrading platform, I knew we had to bring it in,” says Reason. “And it quickly became the sole focus of the company – you should always reinforce strength.

“We started out simply thinking about how we could introduce this gene therapy into the body at the point at which it’s going to do some good. Since it’s totally safe to introduce our technology into cells – if they don’t have excess cholesterol, it does nothing, if they do have excess cholesterol, it gets rid of it – it’s a therapy that should, in principle, work anywhere in the body.”

According to Reason, the key difference between a gene therapy company and a company developing small molecules, for example, is fundamentally a matter of delivery.

“A small molecule company starts out with the approach that they might have something that works and then the preclinical stage of the company is focused on trying to make it work,” he says. “A gene therapy company starts out with something that they are certain will work, but the preclinical stage is all about figuring out how to deliver it. How do we get this thing that works into the part of the body where we want it, in a large enough amount that it’s going work, without it going to places in the body that we don’t want it to go to, and without harming the individual with either the therapy or the vector?”

A gene therapy delivery odyssey

The next few years saw Repair Bio embark on what Reason refers to as an “odyssey” exploring different potential delivery options, starting out with adeno-associated virus (AAV) vectors before ultimately arriving at its LNP mRNA approach.

“The COVID pandemic happened along the way,” he says. “The high-profile efforts to produce mRNA vaccines means that everybody now knows what lipid nanoparticle mRNA therapies are, and the FDA is very familiar with them.”

With many other therapies under development that are using LNPs, Reason says that LNP-mRNA might be thought of as the small molecule of the gene therapy space.

“It stays in the body for only a short time, there’s nothing left in the body afterwards, so doses can be repeated indefinitely. So, in many ways, you can treat it just like a small molecule drug.”

While Repair Bio would ultimately like to work with an approach with longer-lasting effects, Reason explains there are clear benefits to starting with mRNA.

“This is more acceptable for the conservative institutions, so we think this is a good technology for now,” he says. “And it works – it really works. With once-a-week dosing over a six-to-eight-week period the mice exhibit a very profound reversal of disease.”

Positive FDA response

The “profound reversal of disease” seen by Repair Bio includes its recent progress in atherosclerosis, and its initial work in metabolic dysfunction-associated steatohepatitis (MASH), the inflammation of the liver caused by excess cholesterol.

“We first demonstrated positive results in MASH because it’s a liver disease, and in the gene therapy world it’s comparatively easy to deliver things to the liver,” says Reason. “You just put your mRNA into lipid nanoparticles, you don’t even have to optimize all that much, it will just work, so we obtained our proof of concept comparatively early on.”

“We’ve also now demonstrated that we can produce sizable and rapid reversal of atherosclerosis in animal models for both normal, sporadic atherosclerosis and the accelerated version, homozygous familial hypercholesterolemia.”

Armed with this positive preclinical data, the next step for Repair Bio was to produce more robust data and then to “plant a flag” with the FDA.

“We conducted our pre-IND meeting for MASH earlier this year and received very supportive feedback from the FDA,” says Reason. “They offered a few constructive suggestions on our study plans and gave us a clear list of what they want from us for an IND submission, which is exactly what you want the FDA to say. They didn’t object to any of the clinical plans we put forward to test the therapy in humans.”

Towards the clinic, and beyond

Despite the positive FDA feedback on MASH, the recent progress in atherosclerosis means that Repair Bio is now fully focused on getting that program into the clinic.

“Atherosclerosis is the reason we started this program,” says Reason. “Moving ahead, we plan to move ahead into a first in-human clinical trial for patients with homozygous familial hypercholesterolemia. This is a rare genetic disease, so we can look at fast track approval as a possibility.”

“This is the critical juncture. We are now transitioning from a preclinical company that works with mice into a clinical company where we are focused on everything needed to conduct a safe and successful clinical trial in humans. There’s a lot to do, and a lot of funding to raise to get it done. But, right from day one, when we conducted our first AAV study in mice, and we saw that it worked amazingly, we knew that this was going to be a win. It was just a question of how it was going to happen.”

Looking to the future, Reason says that if the company is successful in treating homozygous familial hypercholesterolemia, it could open the door to treating the most serious cases of atherosclerosis in the broader population.

“I believe our technology has the potential to prevent the 10 to 20 million people who die every year from atherosclerosis from dying,” he says. “These are the people with the most severe disease, where there’s no drug combination that’s going to save them. If we can stop those people dying, then after that I could imagine that 20 to 30 years down the line, an advanced version of this technology, will be used by most older people, every five years or so starting in your 40s, and no-one will ever develop atherosclerosis again.”

“But that’s down the line. Focusing on the near future, I will consider it a victory to have completed a Phase 1b clinical trial in which we show that our therapy reverses plaque in humans, at which point everybody in the industry will realize that this is the true inheritor of statins.”