Stomach implant for long-term erythropoietin expression in rats.
To approach the goal of consistent long-term erythropoietin (Epo) expression in vivo, we developed an implantation procedure in which transduced autologous vascular smooth muscle was introduced into rats in a chamber created from a polytetrafluoroethylene (PTFE) ring placed under the serosa of the stomach. The implant became vascularized and permitted the long-term survival of smooth muscle cells expressing Epo. Hematocrits of treated animals increased rapidly and monitored over 12 months gave a mean value of 56.0 +/- 4. 0% (P < .001; n = 9), increased from a presurgery mean of 42.3 +/- 1. 6%. Hemoglobin levels rose from a presurgery mean of 15.2 +/- 0.4 g/dL and for 12 months were significantly elevated with a mean value of 19.5 +/- 1.3 g/dL (P < .001; n = 9). The hematocrit and hemoglobin levels of control animals receiving human adenosine deaminase (ADA)-expressing cells were not significantly different from baseline (P > .05; n = 5). In response to tissue oxygenation, kidney, and (to a lesser extent) liver are specific organs that synthesize Epo. Treated animals showed downregulation of endogenous Epo mRNA in kidney over a 12-month period. The PTFE implant provides sustained gene delivery, is safe, and is minimally invasive. It allows easy engraftment of transduced cells and may be applied generally to the systemic delivery of therapeutic proteins such as hormones and clotting factors.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
D V
DV
Lejnieks
N
N
Ramesh
S
S
Lau
W R
WR
Osborne
D000243:Adenosine Deaminase / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured / Q000637:transplantation; D018076:DNA, Complementary / Q000235:genetics; D004343:Drug Implants; D004867:Equipment Design; D004920:Erythropoiesis; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006400:Hematocrit; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D019868:Kanamycin Kinase / Q000096:biosynthesis; D007668:Kidney / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D009928:Organ Specificity; D011138:Polytetrafluoroethylene; D019736:Prostheses and Implants; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000096:biosynthesis; D013270:Stomach; D014162:Transfection; D016042:Transplantation, Heterotopic
D018076:DNA, Complementary; D004343:Drug Implants; D006454:Hemoglobins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004921:Erythropoietin; D011138:Polytetrafluoroethylene; D019868:Kanamycin Kinase; D000243:Adenosine Deaminase