K. Anwer et al., SYSTEMIC EFFECT OF HUMAN GROWTH-HORMONE AFTER INTRAMUSCULAR INJECTIONOF A SINGLE-DOSE OF A MUSCLE-SPECIFIC GENE MEDICINE, Human gene therapy, 9(5), 1998, pp. 659-670
Citations number
37
Categorie Soggetti
Genetics & Heredity","Biothechnology & Applied Migrobiology","Medicine, Research & Experimental
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.