Development of a recombinant Leishmania major strain sensitive to ganciclovir and 5-fluorocytosine for use as a live vaccine challenge in clinical trials.
To provide a safer live challenge strain for use in clinical vaccine trials, a double drug sensitive strain of Leishmania major was derived using advances in gene targeting technology by stably introducing into the chromosome a modified HSV-1 thymidine kinase gene (tk), conferring increased sensitivity to ganciclovir (GCV), and a Saccharomyces cerevisiae cytosine deaminase gene (cd), conferring sensitivity to 5-fluorocytosine (5-FC). In vitro studies showed that the homozygous L. major (tk-cd+/+) promastigotes were killed by either drug alone, and together the drugs acted synergistically. In vivo infection studies showed that progressively growing lesions in BALB/c mice, caused by L. major (tk-cd+/+), were completely cured by 2 weeks of treatment with either drug alone or in combination. Treated animals showed no signs of reoccurrence of infection for at least 4 months when the experiments were terminated.
Davoudi
Noushin
N
Department of Biotechnology, Pasteur Institute of Tehran, Pasteur Square, Tehran, Iran.
Tate
Celia A
CA
Warburton
Corinna
C
Murray
Angus
A
Mahboudi
Fereidoun
F
McMaster
W Robert
WR
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002986:Clinical Trials as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects* / Q000235:genetics; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000235:genetics
D016052:Protozoan Vaccines; D015774:Ganciclovir; D005472:Fluorouracil