SYSTEMIC EFFECT OF HUMAN GROWTH-HORMONE AFTER INTRAMUSCULAR INJECTIONOF A SINGLE-DOSE OF A MUSCLE-SPECIFIC GENE MEDICINE

A muscle-specific gene medicine is described that provides for long-te rm secretion of biologically active human growth hormone (hGH) from sk eletal muscle into the systemic circulation. The hGH gene medicine is composed of a muscle-specific hGH plasmid expression system complexed with a protective, interactive, noncondensing (PINC(TM)) delivery syst em. The muscle-specific gene expression system, pSK-hGH-GH, was constr ucted by linking the promoter/enhancer regions of chicken skeletal alp ha-actin to hGH gene. C2C12 myoblast transfection with pSK-hGH-GH resu lted in the synthesis of hGH in a muscle-specific manner. Direct injec tion into rat tibialis cranialis muscle of pSK-hGH-GH complexed with a polymeric PINC delivery system, polyvinylpyrrolidone (PVP), produced hGH levels in muscle that were 10- to 15-fold higher compared with pla smid formulated in saline at 14 days post-injection. Intratracheal ins tillation in rat lung of pSK-hGH-GH did not produce significantly dete ctable levels of hGH. In hypophysectomized rats, a single intramuscula r dose of the pSK-hGH-GH/PVP complex resulted in hGH expression and a subsequent increase in serum levels of rat ICE-I and growth. hCH expre ssion and effects on rat serum ICE-I levels were detectable up to 28 d ays after injection of formulated plasmid and effects on growth were d etectable unto 21 days. Anti-hGH antibodies were detectable in serum a t 14 days post-injection, reached a plateau at 21 days, and remained e levated through the study period. Cyclosporin treatment of the pSK-hGH -GH/PVP-injected animals completely inhibited the antibody response an d resulted in increased hGH expression.