Heegon Kim
SCIENCE
A singular focus on
Cholesterol Metabolism Modulators (CMMs)
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.
Cyclodextrins
Cyclodextrin is a ring-structured molecule, composed of six to eight glucoses linked together in a cyclic shape. The cavity of the ring structure exhibits hydrophobicity, whereas the surface exhibits hydrophilicity. Such a ring structure allows it to host hydrophobic molecules such as cholesterol inside the cavity and solubilize them.
Cyclodextrins : CMMs
Cyclodextrins are CMMs that can form complex with excessive intracellular cholesterol, facilitate its distribution, storage, and efflux, which significantly helps cells restore cholesterol homeostasis and prevent cholesterol-induced toxicities.
CMMs in Clinical trials
There are three types of cyclodextrins : alpha-, beta-, and gamma-cyclodextrins. They are composed of six, seven, and eight glucose units, respectively. Alpha-cyclodextrins composed of six glucose units have a small ring structure and therefore cannot effectively interact and form complex with cholesterol. On the other hand, beta-, and gamma-cyclodextrins have cavities large enough to host cholesterol and therefore can be used as CMMs. Hydroxypropyl-beta-cyclodextrin (HPβCD) is a derivative of beta-cyclodextrin and is more soluble and less cytotoxic than natural beta-cyclodextrin. HPβCD is being investigated in clinical trials for diseases including Niemann-Pick type C, Alzheimer's disease, and chronic kidney disease.
Ototoxicity
Despite the promising effects of CMMs on regulating cholesterol homeostasis, ototoxicity can occur following peripheral or central nervous system-directed delivery of HPβCD. It has been experimentally shown in various animal species that both routes can result in the preferential loss of outer hair cells (OHCs) in the cochlea. Ototoxicity caused by loss of OHCs can cause permanent hearing loss, which should be managed with hearing aids.​
