Development of a Gectosome Therapy for Cardiovascular Diseases

Project Summary
Vesicle Therapeutics Inc aims to develop and commercialize a new therapy for homozygous
familial hypercholesterolemia (hoFH). A majority of hoFH is caused by mutations in both alleles
of the gene encoding the LDL receptor (LDLR). Since the efficacy of both statins and PCSK9
antibody therapies largely depends on functional LDL receptors, patients with hoFH show limited
responses to these existing therapies. There is no cure for hoFH, and few options are available
to treat the diseases. Angiopoietin-like 3 (ANGPTL3) has emerged as a possible therapeutic
target for hoFH as individuals deficient in ANGPTL3 do not develop coronary atherosclerotic
plaque. The RNA targeting CRISPR enzyme LwaCas13 can turn off genes by RNA depletion
analogous to RNAi but with very lower rate of off-target gene silencing. The absence of safe
delivery methods currently limits the therapeutic potential of LwaCas13. The Liu laboratory at the
University of Colorado-Boulder developed an innovative intracellular biologics delivery system
called Gectosomes. The overall objective of this phase I STTR project is to demonstrate that
silencing of ANGPTL3 by gectosome delivery of LwaCas13a/ANGPTL3 crRNA is efficacious in
lowering LDL-C with acceptable safety profile in mice. The proposed strategy combines two
innovative technologies for potential clinical translation. The proposed studies are feasible based
on our previous success with gectosome delivery of CRISPR RNP that causes inactivation of
PCSK9 in mouse liver. ANGPTL3 is primarily expressed in hepatocytes and secreted into the
bloodstream. The liver is readily accessible by gectosomes. LwaCas13a-mediated RNA depletion
is reversible and may have fewer safety concerns than gene editing. We will determine the
efficacy and safety of ANGPTL3 suppression by LwaCas13a in mice and this work is necessary
for further studies to advance a potential therapeutic solution for a rare disease.Project Narrative
The goal of this phase I STTR project is to demonstrate that silencing of ANGPTL3 by gectosome
delivery of LwaCas13a/ANGPTL3 crRNA is efficacious in lowering LDL-C with acceptable safety
profile in mice.