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VCRB :: Contents of Volume 57/2002 :: Detailed information


GENETIC ANTISENSE: APPLICATIONS IN AGRICULTURE AND MEDICINE


Norman KELKER1, Elazar RABBANI1, Dakai LIU1, Morton COWAN2,Marcus CONANT2, Barbara THALENFELD1, Dean ENGELHARDT1
1Enzo Therapeutics, Inc., Farmingdale, NY USA2University of California School of Medicine, San Francisko USA


Summary

Genetic antisense is a naturally occurring mechanism for gene regulation.  Regulation is achieved by expression of an antisense gene whose sequence 
is inverted in relation to another gene, a sense gene. Hybridization of the messenger RNA expressed by the antisense gene to the complementary
sense mRNA triggers cellular processes that inactivate translation. Genetic antisense has found wide application in plant research and in commercial
development of new plant varieties. Enzo Therapeutics, Inc. has developed an approach for the treatment of AIDS by using genetic antisense
to protect immune cells from destruction by the AIDS virus (HIV) as a means to prevent the loss of immune competence associated with this disease.
In vitro studies showed that the incorporation into cultured CD4+ cells of three antisense sequences directed against two critical HIV genes
(tar and tat) protected the cells from destruction by the virus.  Based on these results, a phase 1 clinical trial was initiated.  In an ex vivo protocol,
the three antisense genes were incorporated into a Moloney Murine Leukemia Virus (MMLV) vector and delivered to CD34+ blood stem cells that
had been removed from HIV patients. The treated stem cells were returned to the patients, and the patients have been monitored for two years.
All patients survived the procedure with no adverse effects. After two years all patients express antisense RNA in mature CD4+ cells and in CD34+
stem cells in bone marrow indicating that antisense-expressing stem cells have engrafted and are differentiating into mature CD4+ cells.
Phase 2 clinical trials to measure treatment effectiveness are beginning at this time. 



keywords: AIDS, genetic antisense, gene expression

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