Lowering LDL cholesterol levels by antisense oligonucleotide induced alternative splicing of Apolipoprotein B
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
People with high levels of cholesterol are at higher risk of having heart attacks and strokes. Treatments that lower the levels of cholesterol have been shown to protect against these diseases, thereby saving lives. This project will look into how we can use a new drug called an antisense oligonucleotide to lower the level of cholesterol in the blood and therefore perhaps to reduce the risk of heart attacks and strokes.
Technical Summary
Hypercholesterolaemia and high LDL levels cause cardiovascular disease, the major killer in the developed world. Currently licensed treatments for hypercholesterolaemia have many shortcomings: there is a need for alternative therapies to lower cholesterol. Altering the expression of Apolipoprotein B (APOB) has emerged as a key method to accomplish this goal. APOB is the principal structural apolipoprotein in LDL, VLDL, IDL and chylomicron particles. Antisense oligonucleotides (ASOs) which induce alternative splicing of APOB exon 27 are able to generate a truncated APOB isoform, APOB87(SKIP27). Truncation of APOB100, as seen in patients with hypobetalipoproteinaemia, causes major reductions in total and LDL cholesterol levels. ASO-induced alternative splicing will be a useful therapy to reduce circulating LDL and cholesterol levels, without the drawbacks associated with methods that generally down-regulate all isoforms of APOB. In this project, we propose to: (1) optimize the configuration of ASOs and the skipping effect in vitro; and (2) assess the effects of injected optimized ASO on circulating LDL and cholesterol levels in a transgenic mouse model of hypercholesterolaemia and atherosclerosis. Completion of these objectives would validate this ASO-based compound as a therapy for hypercholesterolaemia.