Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer.
Stable delivery of a therapeutic protein under pharmacologic control was achieved through in vivo somatic gene transfer. This system was based on the expression of two chimeric, human-derived proteins that were reconstituted by rapamycin into a transcription factor complex. A mixture of two adeno-associated virus vectors, one expressing the transcription factor chimeras and one containing erythropoietin (Epo) under the control of a promoter responsive to the transcription factor, was injected into skeletal muscle of immune-competent mice. Administration of rapamycin resulted in 200-fold induction of plasma Epo. Stable engraftment of this humanized system in immune-competent mice was achieved for 6 months with similar results for at least 3 months in a rhesus monkey.
Ye
X
X
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA 19104, USA.
Rivera
V M
VM
Zoltick
P
P
Cerasoli
F
F
Schnell
M A
MA
Gao
G
G
Hughes
J V
JV
Gilman
M
M
Wilson
J M
JM
D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004921:Erythropoietin / Q000008:administration & dosage / Q000097:blood / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006400:Hematocrit; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018482:Muscle, Skeletal; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D020123:Sirolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics*
D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D004921:Erythropoietin; D020123:Sirolimus