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HUMAN HEALTH
Pipeline overview
Kidney disease
Cardiovascular disease
Neurodegnetaive disease
IND-enabling
Chronic kidney disease
Preclinical
Atherosclerosis
Preclinical
Alzheimer's disease
Niemann-Pick Type C
Parkinson's disease
Pipeline overview
Chronic kidney disease
Chronic kidney disease
Chronic kidney disease (CKD) is a long-term condition where the kidneys don't work as well as they should. More than 800 million people worldwide and 35 million people in the United States are living with CKD as of 2021. In other words, more than 1 in 8 of adults worldwide are likely to have CKD. Whereas renin-angiotensin system (RAS) inhibitors are commonly used for the treatment of CKD, they have limited efficacy in slowing down the progression of CKD, leaving great unmet meidcal need.
Development stage
Medical needs
Mounting evidence suggests that accumulation of cholesterol in the kidney can cause pathogenesis and progression of kidney disease. Dysregulated cholesterol homeostasis is observed in prevalent (e.g., diabetic kidney disease), as well as in less prevalent (e.g., focal segmental glomerulosclerosis and Alport syndrome) renal diseases. However, there is no treatment that can directly mediate cholesterol efflux within the kidney.
Mechanism of action
In various disease models including diabetic kidney disease, focal segmental glomerulosclerosis, and Alport syndrome, downregulation of ATP-binding cassette transporter (ABCA-1)-mediated cholesterol efflux was observed. In the aforementioned models, cyclodextrin has shown to help clearance of cholesterol in the kidney and exert renoprotective effects, in part by upregulating ABCA-1 in the kidney. RN-005 has shown promising effects in upregulating ABCA-1 in kidney cells.
References
- Cyclodextrin Protects Podocytes in Diabetic Kidney Disease (Diabetes, 2013)
- Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury (Journal of Clinical Investigation, 2016)
- Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis (Kidney International, 2018)
Atherosclerosis
Atherosclerosis
Atherosclerosis is the chronic build up of plaques within your artery, which are composed of cholesterol, fats, inflammatory cells and other substances. The growth of plaques leads to thickening or hardening of the artery and they can end up causing heart attack, stroke, and peripheral vascular disease. Atherosclerosis is the leading cause of death globally.
Development stage
Medical needs
Clinically, the most successful approach to manage atherosclerosis is to lower blood low-density lipoprotein-cholesterol (LDL-C) level using statins. However, even though statin therapy can reduce the risk of clinical events by ~30%, the majority of patients (~70%) still suffer from residual risk. Many patients on statin therapy have clinical events despite successful reductions in LDL-C. Some patients do not respond to statin therapy, failing to achieve low LDL-C level. Therefore, the development of new treatment options that can be used in addition or alternatively to standard care will be crucial to further reduce the residual risk.
Mechanism of action
Whereas statins primarily work in the liver by increasing the LDL-C receptor thereof and reducing LDL-C level in the blood, cyclodextrin can directly remove cholesterol from atherosclerotic plaques. It has been demonstrated that cyclodextrin reduces cholesterol content, reprogram macrophages to promote cholesterol efflux, and exert significant anti-inflammatory effects within plaques. RN-005 exhibits excellent efficacy in solubilizing free cholesterol and inducing cholesterol efflux by macrophages. Having a different mechanism of action from statin and low toxicity, RN-005 will provide a novel and safe treatment option for patients with atherosclerosis.
References
- Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming (Science translational Medicine, 2016)
- Cyclodextrin polymer improves atherosclerosis therapy and reduces ototoxicity (Journal of Controlled Release, 2020)
- Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy (ACS Nano, 2020)
Alzheimer's disease
Alzheimer's disease is the most common type of dementia. Patients with Alzheimer's exhibit an irreversible, progressive neurologic disorder, resulting in loss of memory and other cognitive functions. It is the 6th leading cause of death and affects more than 5.8 million people in the United States.
Alzheimer's disease
Development stage
Medical needs
Although there is medication that can temporarily reduce the symptoms, there is no treatment that can reverse or stop AD. Therapies that target amyloid beta, one of the hallmarks of Alzheimer's, have all failed in clinical trials. Therapies that target tau are in the early clinical development. Growing evidence suggests that abnormal cholesterol metabolism can contribute to the pathogenesis of AD. Many of the known risk factors for Alzheimer's are associated with cholesterol metabolism, such as elevated levels of plasma cholesterol and ApoE genotypes.
Mechanism of action
Although the exact mechanism of action is not known, it is demonstrated that cyclodextrin can improve cholesterol metabolism in the brain and exert neuroprotection effect in Alzheimer's disease model. HPβCD has shown encouraging results in patients with late onset Alzheimer's disease in a Phase 1 clinical trial and received IND clearance from the U.S. FDA for a Phase 2 study in December 2021. We aim to study whether RN-005 can provide a more effective and safe option than HPβCD.
References
- Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons (PNAS, 1998)
- Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease (Journal of Experimental Medicine, 2012)
- Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice (Human Molecular Genetics, 2017)
Niemann-Pick Type C
Niemann-Pick Disease Type C (NPC) is a rare progressive genetic disorder characterized by dysfunction of NPC1 protein leading to inability of the body to transport cholesterol and other fatty substances inside of cells. Abnormal cholesterol accumulation in the major organs lead to organ dysfunction, organ failure, and death.
Niemann-Pick Type C
Development stage
Medical needs
Miglustat is the first and only specific drug approved for NPC in Europe, Canada and Japan. While Miglustat has shown to alleviate disease symptoms while attenuating neurodegeneration, some studies suggest its limited efficacy in NPC. In the US, the FDA declined its approval, requiring for more data. Hydroxypropyl-beta-cyclodextrin (HPβCD) has been used compassionately to treat patients with NPC and is undergoing clinical trials. HPβCD has shown to facilitate cholesterol transport inside of cells and its efflux. HPβCD is given to patients through either intrathecal or intravenous administration. Unfortunately, permanent hearing loss can occur following HPβCD therapy, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs).
Mechanism of action
Cyclodextrin has shown to reduce both cholesterol and sphingolipid storage within cells and to prolong survival in NPC animal models. RN-005 has shown cholesterol efflux efficacy superior to HPβCD.
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