PHARMACOLOGICAL CONTROL OF A HUMANIZED GENE-THERAPY SYSTEM IMPLANTED INTO NUDE-MICE

Systemic delivery of specific therapeutic proteins by a parenteral rou te of administration is a recognized practice in the management of sev eral gene defects and acquired diseases, As an alternative to repetiti ve parenteral administration, gene therapy may provide a novel means f or systemic delivery of therapeutic proteins while improving patient c ompliance and therapeutic efficacy, However, for gene therapy to be an efficacious and safe approach to the clinical management of such dise ases, gene expression must be tightly regulated, These investigations demonstrate precise in vivo control of protein expression from cells t hat are engineered to secrete human growth hormone (hGH) in response t o stimulation by rapamycin, The cells were implanted intramuscularly i nto nu/nu mice and stimulated by intravenous or oral administration of rapamycin, In vivo experiments demonstrate that the activity and phar macokinetics of rapamycin determine the level of serum hGH that result from the engineered cells, In addition, responsiveness of the cells t o rapamycin, number of cells implanted, hGH expression kinetics, and t he pharmacokinetics of hGH itself, also influence the circulating leve ls of hGH after rapamycin stimulation, Controlled manipulation of seve ral of these parameters, either independently or in combination, allow s for precise regulation of circulating hGH concentration in vivo.