ACCUMULATION OF HUMAN APOLIPOPROTEIN-E IN RAT PLASMA AFTER IN-VIVO INTRAMUSCULAR INJECTION OF NAKED DNA

Naked DNA was found to be incorporated and consistently expressed afte r in vivo direct injection into striated muscle. In addition to the lo cal expression of muscle-related or exogenous proteins, intramuscular direct gene transfer may be a useful tool to deliver recombinant prote ins into the blood stream. However, no direct demonstration of recombi nant protein secretion from muscle to the circulation has been reporte d thus far. We have injected a naked plasmid DNA containing the human receptor-binding defective apo-E2 cDNA, under the control of CMV promo ter, into the quadriceps of Yoshida rats, affected by hereditary hyper cholesterolemia and altered LDL-receptor activity. Plasma accumulation of human apo-E2 was demonstrated for at least 45 days after injection . On the contrary, the expression of the normal human apo-E3, injected into the muscle of normal Wistar rats, was demonstrated only in the a rea of muscular injection and not in the blood plasma. Endogenous rat apo-E expression was not affected by the exogenous human apo-E2 produc tion. Our results demonstrate the availability of intramuscular direct gene transfer as a safe and simple method for the chronic systemic de livery of recombinant proteins to the circulation, although further im provements are needed in order to enhance the efficiency and stability of expression. (C) 1994 Academic Press, Inc.