1113. Spliceosome Mediated RNA Trans-Splicing (SMaRT|[trade]|) Strategy To Increase the Production of Human Apolipoprotein (ApoA1)

Cardiovascular disease (CVD) is the most common cause of death in Western societies, and its worldwide prevalence is increasing. A very strong predictor of CVD risk is the plasma concentration of high-density lipoprotein (HDL) or of its major protein component, ApoA-1. HDL and ApoA-1 levels exhibit an inverse relationship with the development of atherosclerosis and coronary heart disease1,2,3 and exogenous ApoA1 and HDL protect against atherosclerosis and plaque development 4,5,6,7. The present study was undertaken to determine if RNA trans-splicing could be used to increase blood levels of human ApoA-1 (hApoA1). To this end we targeted a pre-trans-splicing molecule (PTM) encoding human ApoA1 to the highly abundant albumin pre-messenger RNA (pre-mRNA). Trans-splicing between the PTM and the albumin pre-mRNA results in the production of human ApoA1 protein with two residual albumin amino acids. This fusion protein was expressed, processed and secreted as well as authentic hApoA1 and indeed the fusion protein had full activity in ATP-binding cassette transporter protein (ABC1)-mediated transfer of cellular cholesterol efflux assays.