title: Systemic effect of human growth hormone after intramuscular injection of a single dose of a muscle-specific gene medicine.
abstract: 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.
authors.affiliation: GeneMedicine, Inc., The Woodlands, TX 77381-4248, USA.
authors.forename: K
authors.initials: K
authors.lastname: Anwer
authors.forename: M
authors.initials: M
authors.lastname: Shi
authors.forename: M F
authors.initials: MF
authors.lastname: French
authors.forename: S R
authors.initials: SR
authors.lastname: Muller
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: B L
authors.initials: BL
authors.lastname: Proctor
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: R J
authors.initials: RJ
authors.lastname: Mumper
authors.forename: A
authors.initials: A
authors.lastname: Singhal
authors.forename: A P
authors.initials: AP
authors.lastname: Rolland
authors.forename: H W
authors.initials: HW
authors.lastname: Alila
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002645:Chickens; D016572:Cyclosporine; D016503:Drug Delivery Systems; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D013006:Growth Hormone / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007016:Hypophysectomy; D007273:Injections, Intramuscular; D018482:Muscle, Skeletal / Q000378:metabolism*; D009928:Organ Specificity; D010957:Plasmids / Q000008:administration & dosage; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000906:Antibodies; D011108:Polymers; D016572:Cyclosporine; D013006:Growth Hormone