Strategies for hematopoietic stem cell gene therapy: insights from computer
simulation studies
JL Abkowitz, SN Catlin and P Guttorp
Department of Medicine, University of Washington, Seattle 98915-77100, USA.
We simulated gene therapy using parameters derived from the analysis of
autologous transplantation studies in glucose-6-phosphate dehydrogenase
heterozygous cats to determine how hematopoietic stem cell (HSC) biology
might influence outcomes. Simulation illustrates that a successful
experiment can result by chance and may not be the repeated outcome of a
specific protocol design or technical approach. As importantly, in many
simulated gene therapy experiments where 1, 2, or 6 of 30 transplanted HSC
were labeled, there was significant variation in the contribution from
marked clones over time. Variability was minimized in simulations in which
large numbers of HSC were transplanted. Strategies that may permit
consistent clinically successful results are presented. Taken together,
these simulation studies demonstrate that the in vivo behavior of HSC must
be considered when optimizing approaches to gene therapy in large animals,
and perhaps by extension, in humans.
Volume 89,
Issue 9,
pp. 3192-3198,
05/01/1997
Copyright © 1997 by The American Society of Hematology
