Delivery of a therapeutic protein by immune-privileged Sertoli cells.
Immune-privileged Sertoli cells survive long term after allogeneic or xenogeneic transplantation without the use of immunosuppressive drugs, suggesting they could be used as a vehicle to deliver therapeutic proteins. As a model to test this, we engineered Sertoli cells to transiently produce basal levels of insulin and then examined their ability to lower blood glucose levels after transplantation into diabetic SCID mice. Mouse and porcine Sertoli cells transduced with a recombinant adenoviral vector containing furin-modified human proinsulin cDNA expressed insulin mRNA and secreted insulin protein. Transplantation of 5-20 million insulin-expressing porcine Sertoli cells into diabetic SCID mice significantly decreased blood glucose levels in a dose-dependent manner, with 20 million Sertoli cells decreasing blood glucose levels to 9.8 ± 2.7 mM. Similar results were obtained when 20 million insulin-positive, BALB/c mouse Sertoli cells were transplanted; blood glucose levels dropped to 6.3 ± 2.4 mM and remained significantly lower for 5 days. To our knowledge, this is the first study to demonstrate Sertoli cells can be engineered to produce and secrete a clinically relevant factor that has a therapeutic effect, thus supporting the concept of using immune-privileged Sertoli cells as a potential vehicle for gene therapy.
Halley
Katelyn
K
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Dyson
Emily L
EL
Kaur
Gurvinder
G
Mital
Payal
P
Uong
Peter M
PM
Dass
Brinda
B
Crowell
Sherry N
SN
Dufour
Jannette M
JM
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy*; D016503:Drug Delivery Systems; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012708:Sertoli Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology / Q000637:transplantation*; D013552:Swine
D001786:Blood Glucose; D007328:Insulin