Systemic effect of human growth hormone after intramuscular injection of a single dose of a muscle-specific gene medicine

• Published in: Human gene therapy Vol. 9; no. 5; p. 659
• Main Authors: Anwer, K, Shi, M, French, M F, Muller, S R, Chen, W, Liu, Q, Proctor, B L, Wang, J, Mumper, R J, Singhal, A, Rolland, A P, Alila, H W
• Format: Journal Article
• Language: English
• Published: United States 20.03.1998
• Subjects: Actins - genetics; Animals; Antibodies - immunology; Chickens; Cyclosporine; Drug Delivery Systems; Gene Expression; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Growth Hormone - administration & dosage; Growth Hormone - biosynthesis; Growth Hormone - genetics; Growth Hormone - immunology; Humans; Hypophysectomy; Injections, Intramuscular; Muscle, Skeletal - metabolism; Organ Specificity; Plasmids - administration & dosage; Polymers; Rats; Rats, Sprague-Dawley
• ISSN: 1043-0342; 1557-7422
• DOI: 10.1089/hum.1998.9.5-659

A muscle-specific gene medicine is described that provides for long-term secretion of biologically active human growth hormone (hGH) from skeletal muscle into the systemic circulation. The hGH gene medicine is composed of a muscle-specific hGH plasmid expression system complexed with a protective, interactive, non-condensing (PINC) delivery system. The muscle-specific gene expression system, pSK-hGH-GH, was constructed by linking the promoter/enhancer regions of chicken skeletal alpha-actin to hGH gene. C2C12 myoblast transfection with pSK-hGH-GH resulted in the synthesis of hGH in a muscle-specific manner. Direct injection 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 plasmid formulated in saline at 14 days post-injection. Intratracheal instillation in rat lung of pSK-hGH-GH did not produce significantly detectable levels of hGH. In hypophysectomized rats, a single intramuscular dose of the pSK-hGH-GH/PVP complex resulted in hGH expression and a subsequent increase in serum levels of rat IGF-I and growth. hGH expression and effects on rat serum IGF-I levels were detectable up to 28 days after injection of formulated plasmid and effects on growth were detectable unto 21 days. Anti-hGH antibodies were detectable in serum at 14 days post-injection, reached a plateau at 21 days, and remained elevated through the study period. Cyclosporin treatment of the pSK-hGH-GH/PVP-injected animals completely inhibited the antibody response and resulted in increased hGH expression.