Therapeutic Approach to Clear sdLDL from Circulation

Project Abstract Cardiovascular Disease (CVD) is a significant threat in the United States and developing countries across the globe. Widely associated with elevated low density lipoprotein cholesterol (LDL-c), therapeutic interventions are primarily focused on reduction of LDL-c plasma levels. Despite the ability to therapeutically reach these target levels, many patients maintain high cardiovascular risk profiles. A causal contributor to this therapeutic paradox is the development of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants small dense LDL (sdLDL) subclass, all of which are generated by lipolysis of very low density lipoprotein (VLDL) remnants. Notably, increased levels of these highly atherogenic species have been attributed to their content of Apolipoprotein C-III (ApoC-III), a protein that retards their plasma clearance due to inhibition of lipolysis as well as interference with Apolipoprotein E (ApoE)-mediated binding and uptake by hepatic receptors, including heparin sulfate proteoglycans (HSPGs) via syndecan action and the LDL receptor (LDLR). Even though there is a limited understanding of sdLDL vascular pathology, it is clear that elevation in these particles leads to significant CVD risk despite patients achieving desired LDL-c reductions based on the current clinical guidelines. As a potential solution, we are proposing the development of a novel therapeutic approach that capitalizes on the excess of ApoC-III on these particles. This proof-of-concept Phase I work is focused on sdLDL depletion, by reengineering iMBP-001, a proprietary ApoC-III antagonist, to include bioactive ApoE memetic peptides. This dual domain therapeutic candidate can perform highly specific particle recognition and binding through ApoC-III, but then facilitate sdLDL particle clearance via LDL receptor (LDLR) and/or Heparin Sulfate Proteoglycan (HSPG) syndecan uptake. This research program is to progressively narrow the candidate pipeline and culminate in hepatic uptake feasibility testing. Uptake of purified human DiI sdLDL particles in Hep G2 and primary hepatocyte cell lines will be evaluated. The milestone for this program is the identification of at least one dual-domain candidate therapeutic molecule that demonstrates a ≥ 5-fold increase in cellular uptake and a ≥ 10% reduction in Apolipoprotein B concentration in the surrounding biological milieu versus controls. The satisfaction of this milestone would lead to a SBIR Phase 2 application that would include further ApoE memetic peptide evaluation, establishment of a scaled non-GMP manufacturing expression system and initiation of non-GLP preclinical testing.