Lecture on Oxidized Cholesterol and Cardiovascular Disease

Introduction

• Learned about oxidized cholesterol from Aubrey as a graduate student.
• Focus on the problem of oxidized cholesterol, specifically 7-keto-cholesterol (7KC).
• 7KC is a toxic form of cholesterol linked to aging and cardiovascular disease, particularly atherosclerosis.

Mechanism of Atherosclerosis

• Macrophages consume lipids at lesion sites in arteries.
• Excessive consumption leads to 7KC, disrupting lysosomes in macrophages.
• Macrophages become "foam cells," contributing to plaque formation.
• Goal: Remove 7KC to rejuvenate macrophages and restore their function.

Current Treatments for Cardiovascular Disease

• Blood thinners and lipid-lowering therapies are used to reduce cardiovascular event likelihood.
• New treatments target inflammation and genetic factors.
• Seeking to advance "damage reversal" therapies by targeting 7KC.

Research on 7KC

• Studies link 7KC levels with cardiovascular disease risk, though fewer studies exist compared to LDL.
• 7KC association with disease makes it a promising target for new therapies.

Cyclodextrins as a Solution

• Cyclodextrins are cyclic carbohydrates explored for cholesterol-binding properties.
• Computational modeling showed strong 7KC binding with beta cyclodextrins in a "head-to-head" configuration.
• Developed new cyclodextrins, significantly more potent and specific for 7KC over regular cholesterol.
• Importance of specificity to avoid stripping too much cholesterol and causing cell toxicity.

Experimental Results

• Cyclodextrin treatment reversed macrophage foam cell formation.
• Treated macrophages regained normal appearance and function.
• Lead drug, UDP003, effectively reverses 7KC effects.
• Gene expression profiling shows restoration of key lipid metabolism pathways.

Clinical Development and Trials

• Transitioning from R&D to clinical stage.
• Phase 1 trial planned in Adelaide, Australia, focusing on safety and biomarkers.
• Phase 2 will assess efficacy on coronary artery disease using non-invasive imaging.
• Potential for wider applications if successful in various cardiovascular conditions.

Manufacturing and Regulatory Progress

• Scaled manufacturing to kilogram scale, developed liquid formulations.
• Regulatory interactions in the UK and US.
• Clinical trial application being submitted in Australia.

Cardiologist Collaborations

• Collaboration with top cardiologists, including Steve Nichols.
• Nichols’ involvement facilitates trial execution in Australia.

Future Directions for the Drug

• Exploring applications in stroke recovery, Alzheimer's, and orphan diseases.
• Cyclodextrin technology could be applied to other diseases and conditions.
• Seeking partnerships for broader applications, including non-aging related issues.

Conclusion

• Excitement about potential breakthroughs in reversing cardiovascular disease.
• Continued development and potential expansion into other therapeutic areas using cyclodextrin technology.