Fig. 6: In vivo somatic cell gene correction strategies involve tradeoffs between efficiency, precision, progenitor affinity, and editor stability.

a In silico Gene Therapy Efficacy Model (GETEM) for Pompe disease correction in a developing infant. Schematic showing gene correction for two diseased alleles in a liver indicating correction of alleles, a1 and a2, by genome editors 1 and 2 to form gene-corrected cells capable of secreting GAA to enzymatically correct other unedited cells. Secreted GAA is also absorbed by striated muscle tissue (both heart and skeletal muscle). b Percentage of normal cardiac tissue within a developing heart of a Pompe diseased infant after the administration of six doses of genome editors at 23.9 mg/kg. c Cell numbers indicating growth of diseased, normal, and precisely-edited cells in the gene-edited liver depot after the administration of 6 doses of genome editors at 23.9 mg/kg. d Distribution of genotypes in the gene-edited liver depot after the administration of 6 doses of genome editors at 23.9 mg/kg. e Sensitivity analysis of the model indicating the absolute values of parameter sensitivity of tissue morphogenesis factors, genome editor factors, and cell/tissue biology intrinsic factors. f Tradeoff between genome editor efficiency and genome editor stability, focusing on the percentage of enzymatically cross-corrected heart tissue. Heatmap indicates that lower efficiency editors could be efficacious if the extracellular editor stability increases. g Tradeoff between genome editor efficiency and precision, focusing on the percentage of enzymatically cross-corrected heart tissue. Heatmap indicates that lower efficiency editors can be efficacious if higher precision editors are used. h Tradeoff between increasing genome editor dose and progenitor affinity, focusing on the percentage of enzymatically cross-corrected heart tissue. i Using GETEM, heatmap indicating tradeoff in heart muscle correction in the developing infant between the degradation rates of GAA in the serum and cellular GAA, indicating that stabilization of GAA in the serum can improve clinical outcome (gray arrowhead indicates pre-stabilization, black arrowhead indicates post-stabilization). Simulation results for liver and skeletal muscle are shown in Supplementary Figs. 11 and 12.