Renatus Makes Safe Cholesterol Metabolism Modulators

In 2021, while Heegon Kim was conducting postdoctoral research at Northwestern University’s Feinberg School of Medicine, he noticed that there was a lack of effort to make cyclodextrins safer and he found limited literature online on that subject. So, he decided to return to Korea and start his own company, Renatus, to address this gap. 

Cyclodextrins are cyclic oligosaccharides that are known as effective modulators of cholesterol metabolism, indicated for various cholesterol-driven diseases, but they can have serious side effects such as hearing loss. 

“I wanted to address such issues and create a better cyclodextrin because people have been using traditional ones like hydroxypropyl-ß cyclodextrin (HPßCD). We are not limited to using the beta class; we are also using other classes of cyclodextrins.  Our drug candidates are showing comparable or even superior efficacy without significant side effects in varying preclinical disease models,” Kim says.

There are two main mechanisms of action of cyclodextrin. First it depletes cholesterol from the plasma membrane. Cholesterol is hydrophobic and about 80% or even more of it is located in the plasma membrane of the cell, with the rest in the cytoplasm. Cyclodextrin interacts with cholesterol, increases its solubility, and depletes the cholesterol from the plasma membrane. To balance the effect of cholesterol moving out of the plasma membrane, the cholesterol in the cytoplasm travels to the membrane, thus decreasing the overall cellular content of cholesterol. The second mechanism of action involves cyclodextrin getting inside the cells by endocytosis and then working from there. When there's excessive cholesterol in a diseased cell, it accumulates in places like the endosomal-lysosomal system and causes inflammation instead of being stored or moving out of the cell by efflux mechanisms. Once inside the cell, cyclodextrin can interact with cholesterol directly, and by solubilizing the cholesterol, it helps distribute it inside the cell and activates the efflux mechanisms. 

But there’s a problem with the first mechanism of action. “Let's say cyclodextrin depletes cholesterol from the plasma membrane very quickly, but the transport of cholesterol inside the cells to the membrane takes some time,” says Kim. “So, there's an imbalance in the timing.” 

Membrane integrity is compromised when the cells lack plasma membrane cholesterol   and some cells are very susceptible to it, leading to apoptosis and even cell death. In the cochlea, outer hair cells respond to sound-induced vibrations and amplify them. The hair cells are structured to be very sensitive to the membrane stimulus and at the same time they are very susceptible to membrane disruption. When the cyclodextrin, HPßCD, is injected and starts depleting membrane cholesterol, the outer hair cells become extremely vulnerable to it.  This can cause irreversible hearing loss or ototoxicity, which is the dose limiting toxicity of the cyclodextrin in the clinic. 

This is the problem Renatus is working to solve. There are three classes of cyclodextrins: alpha, beta, and gamma. Beta has the highest affinity with cholesterol, says Kim, but also tends to deplete plasma membrane cholesterol fast. Gamma cyclodextrin has relatively low affinity to cholesterol, and it has much lower tendency to deplete cholesterol from the plasma membrane. 

While several companies are testing beta-cyclodextrins in clinical trials for Alzheimer’s disease, Niemann-Pick type C, and familiar hypercholesterolemia, Renatus is utilizing a range of innovative approaches, including a technology to engineer gamma cyclodextrin to form a stable complex with cholesterol. 

“Cyclodextrin is a ring structured molecule, and when there's one to one interaction with cholesterol, it is not that stable,” Kim says. “We have a technology to cross-link gamma-cyclodextrin monomers to form oligomers that form a very stable complex with cholesterol. Importantly, the oligomer doesn't deplete cholesterol from the plasma membrane, showing preferential and strong affinity for non-membranous cholesterol as a result. By doing that, we've seen that at a very high dose of 8,000 milligram per kilogram, HPßCD causes 50% mortality in mice, with the remaining subjects exhibiting complete hearing loss. In contrast, our compound, RN-005, cross-linked HPγCD, at the same dose, doesn't cause any mortality or ototoxicity.”

By shifting to the second mechanism of action of cyclodextrin, Renatus can overcome the safety issues. RN-005 goes inside the cells and works from within. “We are shifting to the latter mechanism. It is safer, even though it is not rapid depletion of cholesterol,” says Kim. “And the polymer structure gives it some advantages such as a better solubilizing effect and better pharmacokinetics. It is safer, but also shows either similar or better efficacy in modulating cholesterol metabolism.”

In the cell, cyclodextrin upregulates ABCA1 transmembrane protein, which enhances reverse cholesterol transport, and promotes the enzymatic conversion of cholesterol to oxysterols for passive efflux and to esters for storage. 

Renatus’ pipeline includes programs for diabetic kidney disease, focal segmental glomerulosclerosis, Alzheimer’s disease, Niemann-Pick Type C, and atherosclerosis. The lead candidate, RN-005 is in preclinical development with methods patents for indications that include chronic kidney disease and neurodegenerative diseases caused by proteinopathies. The company plans to out-license it for co-development with a larger pharmaceutical company and recently listed RN-005 on the Bioneex drug marketplace platform, with plans to list other candidates as they move to a licensable stage. 

“We are a pharma company dedicated to generating innovative, safe, and effective cholesterol modulators that have potential to improve the quality of life of patients” says Kim. “We are working on many interesting projects and demonstrating the critical roles of cholesterol metabolism in the pathogenesis and progression of varying diseases. We believe that cholesterol and its metabolism is a valuable therapeutic target, offering significant opportunities for innovative treatments that can improve patient outcomes in many diseases.”