STRATEGIES FOR HEMATOPOIETIC STEM-CELL GENE-THERAPY - INSIGHTS FROM COMPUTER-SIMULATION STUDIES

We simulated gene therapy using parameters derived from the analysis o f autologous transplantation studies in glucose-6-phosphate dehydrogen ase heterozygous cats to determine how hematopoietic stem cell (HSC) b iology might influence outcomes. Simulation illustrates that a success ful experiment can result by chance and may not be the repeated outcom e of a specific protocol design or technical approach, As importantly, in many simulated gene therapy experiments where 1, 2, or 6 of 30 tra nsplanted HSC were labeled, there was significant Variation in the con tribution from marked clones over time, Variability was minimized in s imulations in which large numbers of HSC were transplanted. Strategies that may permit consistent clinically successful results are presente d. Taken together, these simulation studies demonstrate that the in vi vo behavior of HSC must be considered when optimizing approaches to ge ne therapy in targe animals, and perhaps by extension, in humans. (C) 1997 by The American Society of Hematology.