SERIAL TRANSPLANTATION SHOWS THAT EARLY HEMATOPOIETIC PRECURSOR CELLSARE TRANSDUCED BY MDR-1 RETROVIRAL VECTOR IN A MOUSE GENE-THERAPY MODEL

The administration of high and repeated doses of chemotherapy has been hampered by the bone marrow toxicity imposed by these drugs. This obs tacle can be circumvented by the introduction of chemotherapy resistan ce genes into the normal marrow cells, which are then transplanted bac k into the patient. To show that this approach can improve our ability to safely deliver high doses of chemotherapy, we used an animal model system to transplant bone marrow cells which have been transduced wit h a safety-modified retrovirus containing human multiple-drug resistan ce (MDR-1) cDNA into lethally irradiated mice. These studies produced mice whose bone marrow and peripheral blood displayed an increased lev el of MDR-1 expression and resistance to the myelotoxic side effects o f Taxol. To determine whether sufficient numbers of early hematopoieti c precursor cells were transduced with the MDR-1 retrovirus so that du rable Taxol-resistant hematopoiesis would result, we serially transpla nted the modified bone marrow cells into each of six successive cohort s of BALB/c mice. Taxol-resistant hematopoiesis with little or no myel osuppression was observed in all six of the cohorts. These data sugges t that very early precursor cells were transduced by the vector. This animal model may be of use in the development of genetic therapy progr ams which use bone marrow to introduce therapeutic molecules into the systemic circulation, since it permits in vivo selection of geneticall y modified hematopoietic progenitor cells. Furthermore, the retroviral vector system we have used could have an immediate impact in the clin ical setting, where it can protect patients from the myelosuppressive side effects of Taxol in advanced stages of human epithelial cancers.