Elevated levels of low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to ischemic cardiovascular disease (CVD), the leading cause of death in the United States and globally. PCSK9, a secretory mammalian serine protease, interacts with low-density lipoprotein receptors (LDLR) on the surface of hepatocytes, leading to the receptor’s internalization and degradation. As LDLR is primarily responsible for removal of LDL-C from circulation, PCSK9 activity decreases expression of LDLR and increases serum levels of LDL-C. Accordingly, gain-of-function PCSK9 mutations lead to autosomal dominant familial hypercholesterolemia. FDA-approved anti-PCSK9 monoclonal antibodies (mAbs) have shown clinical efficacy in LDL-C reduction, lowering plasma LDL-C levels by approximately 60% without adverse events, even in patients receiving maximum dose statins. A significant drawback to anti-PCSK9 mAbs is high list price, limiting affordable access. We have engineered a selfassembling therapeutic peptide (Sle-Pep28) targeting PCSK9 to treat familial hypercholesterolemia, as an affordable alternative to mAb therapies. Sle-Pep28 is formulated as a polymeric hydrogel that gradually releases therapeutic peptides at the subcutaneous implant site. Subcutaneous delivery promotes improved pharmacodynamics over oral and intravenous administration. Promisingly, Sle-Pep28 shows specific, irreversible binding to PCSK9 in surface plasmon resonance (SPR) studies as well as significantly increased LDLR expression in hepatocytes.

Self-assembling peptides to mitigate familial hypercholesterolemia

ACS Fall 2020 Virtual Meeting

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