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TECHNOLOGY

With its mission to provide safe and effective treatment options for patients living with cholesterol-driven diseases, Renatus has focused on deriving next-generation cholesterol metabolism modulators (CMMs) with better safety and efficacy compared to the traditional ones. This will allow broad and safe application of CMMs for various cholesterol-driven diseases.

REBON™ technology

REstricted Bonding for OligomerizatioN

Renatus' REBON™ technology enables generation of a library of novel CMMs with significantly improved affinity for free cholesterol and low affinity for plasma membrane-embedded cholesterol. The features allow preferential removal of intracellular cholesterol by enhancing its metabolism and efflux pathways while inhibiting toxicities induced by plasma membrane disruption. 

 

Whereas the traditional CMM, HPβCD, is being used for multiple indications including Niemann-Pick Type C, Alzheimer's disease and chronic kidney disease, our REBON™ technology in combination with thorough in vitro and in vivo screening assays will allow development of a disease-specific and disease-optimized CMM.

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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.

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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. 

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Also, significant increase in cellular ABCA1 and cholesteryl ester implies cholesterol metabolism enhanced by RN-005. 

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RN-005 exhibits superior cholesterol dissolution

RN-005 exhibits superior ability to bind with and dissolve free cholesterol compared to HPβCD due to its structure designed to form much stable inclusion complex with cholesterol. The improved ability to dissolve cholesterol leads to facilitation of transport, distribution, and metabolism of intracellular cholesterol, as demonstrated in the cholesterol efflux test above.

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RN-005 prevents plasma membrane disruption 

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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.

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RN-005 induces no significant ototoxicity

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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).

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The preferential removal of intracellular cholesterol over plasma membrane cholesterol by RN-005 and other Renatus' CMM candidates will allow broad and safe application of CMMs for various cholesterol-associated diseases.

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