Targeted gene delivery to Kaposi's sarcoma cells via the fibroblast growth factor receptor.
Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidity and mortality. Current chemotherapeutic regimens are associated with a dismal prognosis. In an effort to develop a new approach to KS treatment, we devised a gene therapy-based adenovirus retargeting schema that redirects the adenovirus to fibroblast growth factor receptors endogenously present on the cell surface of KS cells. By using a bifunctional conjugate consisting of a blocking antiadenoviral knob Fab linked to basic fibroblast growth factor, FGF2, the gene transduction of KS cells was enhanced 7.7-44 fold; recombinant adenoviruses encoding either the firefly luciferase reporter gene, or the herpes simplex thymidine kinase gene, demonstrated quantitative enhancement of expression in the KS cell lines. In this regard, two KS cell lines that were previously refractory to native adenovirus transduction could be successfully transduced by the addition of the conjugate. This study thus addresses the utility of adenoviral retargeting to the FGF receptor in KS cells that are ordinarily transduction refractory to standardized approaches and allows practical development of gene therapy approaches for the treatment of human KS.
Goldman
C K
CK
Gene Therapy Program, University of Alabama at Birmingham, 35294, USA.
Rogers
B E
BE
Douglas
J T
JT
Sosnowski
B A
BA
Ying
W
W
Siegal
G P
GP
Baird
A
A
Campain
J A
JA
Curiel
D T
DT
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000256:Adenoviridae / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000276:immunology / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D014162:Transfection / Q000379:methods*; D014407:Tumor Cells, Cultured / Q000821:virology
D007140:Immunoglobulin Fab Fragments; D017468:Receptors, Fibroblast Growth Factor; D008156:Luciferases