867. Spliceosome Mediated RNA Trans-Splicing To Increase Blood Levels of Apolipoprotein A-I and High Density Lipoproteins

Low levels of high density lipoprotein (HDL) represent an important predictor of cardiovascular disease risk1,2. An increase of 1mg/dl in HDL correlates with a risk reduction of cardiovascular disease of 2|[ndash]|3%3. We have adapted spliceosome mediated RNA trans-splicing technology (SMaRT|[trade]|) to trans-splice the sequences of wild type human apolipoprotein A-I (apoA-I) into the highly abundant albumin pre-mRNA in hepatocytes with the objective of transiently increasing blood levels of HDL. ApoA-I is the major protein component of HDL. We targeted a pre-trans-splicing molecule (PTM) to bind to specific sequences in the first intron of mouse albumin pre-mRNA. The bound PTM will then trans-splice, inserting sequences for human ApoA-I into intron 1 of albumin pre-mRNA. With trans-splicing, apoA-I would be made in hepatocytes, the same cells that naturally synthesize apoA-I.