Heegon Kim
CHOLESTEROL
Cholesterol plays vital roles in our body. As an essential building block of cell membranes, cholesterol is fundamental for biosynthesis, integrity, and functions of the biological membranes. It is also crucial for synthesis of hormones, vitamin D, and other substances. However, dysregulated cholesterol homeostasis and excessive accumulation of cincholesterol can increase risk of having diseases including chronic kidney disease, Alzheimer's disease, and atherosclerosis. Unfortunately, there is no drug in the market that can directly target cholesterol and help normalization of cholesterol homeostasis, implying high unmet medical needs. Renatus is focused on developing cholesterol metabolism modulators (CMMs) that can directly target cholesterol and normalize the dysregulated cholesterol homeostasis, addressing the unmet medical needs.
Cholesterol homeostasis
Proper intracellular distribution among subcellular organelles and the plasma membrane, storage in the cholesteryl ester form, and efflux through passive and active pathways should well coordinate for regulation of cholesterol homeostasis.
Dysregulated cholesterol homeostasis
Various factors including aging, diabetes, and genetics can cause cholesterol metabolic dysfunction. Dysregulation of cholesterol homeostasis and accumulation of excessive cholesterol can result in cholesterol-induced toxicities, which can contribute to developing various diseases such as chronic kidney disease, cardiovascular disease, and neurodegenerative disease.
Lead product : RN-005
RN-005 is a proprietary CMM developed by Renatus, which is designed to minimize ototoxicity, the major dose-limiting side effect of the traditional CMM, HPβCD, and to improve cellular cholesterol efflux.
RN-005 and other candidates are being tested in various cholesterol-driven diseases including chronic kidney disease, Alzheimer's disease, atherosclerosis and others.
RN-005 promotes cellular cholesterol efflux
In cells diseased with excessive cholesterol accumulation, RN-005 effectively induces cholesterol efflux, which is about 5 times more potent than HPβCD. Enhancement of cholesterol efflux by RN-005 has been demonstrated in various cell lines.
Also, significant increase in cellular ABCA1 and cholesteryl ester implies cholesterol metabolism enhanced by RN-005.
RN-005 prevents plasma membrane disruption
Disruption of plasma membrane is known as the main cause of CMM-induced outer hair cell death and ototoxicity.
Despite its superior ability to bind with free cholesterol, RN-005 is designed to not to interact with cholesterol within the plasma membrane. Plasma membrane cholesterol extraction by RN-005 is about 5-times lower than HPβCD. As a result, cytotoxicity and hemolytic activity caused by membrane disruption are significantly low with RN-005.
RN-005 induces no significant ototoxicity
To study whether reduced cellular membrane disruption leads to protection from hearing loss, RN-005 was injected at a very high dose (8,000 mg/kg) into mice. An auditory brainstem response (ABR) test, a safe and painless test to see how the hearing nerves and brain respond to sounds, shows that RN-005 does not induce any increase in hearing thresholds as opposed to HPβCD. Furthermore, histological analysis confirms no significant loss of outer hair cells after RN-005 treatment as opposed to 40% loss after HPβCD treatment.
RN-005 exhibits superb systemic safety
RN-005 not only significantly reduces ototoxicity but also shows greater systemic safety as measured by body weight change and behavioral score at a high dose (8,000 mg/kg).
