In July 1990, Dr. Martin J. Cline at UCLA headed another highly controversial human trial designed to treat β-thalassemia without institutional approval. The experiment involved the removal of bone marrow cells from two patients in Jerusalem and Naples, and their subsequent transformation in vitro with plasmids carrying the β-globin gene and the herpes simplex virus thymidine kinase (HSV-tk) gene expected to provide a selective proliferative advantage to marrow cells once these were transplanted back into the patients.
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OneoftheearliestgenetherapytrialswasconductedbyGrossmanetal.,in1992totreatapatientwithfamilialhypercholesterolemiabygeneticmodification in vivoofculturedhepatocytes.
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According to the Journal of Gene Medicine (2012), during the 1990s, for 69% of human patients, the main target disease by gene therapy was cancer. But only 10% of protocols reached phase III.
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The rather discouraging decade of the 1990s finished badly in September 1999 with the widely publicized death of Jesse Gelsinger, an 18-year-old man undergoing gene therapy for the kidney genetic disease ornithine transcarboxylase deficiency (OTCD) — a shadow over the whole field of gene-based therapies.
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Since2003,5patientswithX-linkedseverecombinedimmunodeficiencydevelopedaleukemia-likesyndromenearly2.5-5yearsafterbeingtreatedwithretroviralgenetherapy.4outofthese5patientsareinremissionafterchemotherapyandingoodconditionwithdetectablegenemarkinginperipheralbloodcells.Initiationoftransformationwastracedbacktoinsertionalactivationoftheproto-oncogeneLMN2,atranscriptionalcofactor,whichinadditiontoitsroleinHSCdevelopment,promotesself-renewalofcommittedTcellswhenoverexpressedtherebyfacilitatingtheacquisitionofadditionalmutations.
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