Figure 8.

Effect of cell doubling time and target protein half-life on the ability to maintain persistent gene silencing. All plots represent predicted mRNA (dashed lines) and protein (solid lines) knockdown in transfected cells using the baseline in vitro parameters given in Table 2, a transfection time of 5 h, and an initial number of dividing and nondividing cells equal to 5 × 10⁴ and 1.5 × 10⁵, respectively. (A) Dose of 100 nM siRNA every 3 days with a target protein half-life of 2 h (kdegprot = 0.35 h⁻¹) in cells with a doubling time of 1 day (kgrowth = 0.029 h⁻¹). (B) Dose of 100 nM siRNA every 3 days with a target protein half-life of 48 h (kdegprot = 0.014 h⁻¹) in cells with a doubling time of 1 day (kgrowth = 0.029 h⁻¹). (C) Dose of 100 nM siRNA every 7 days with a target protein half-life of 2 h (kdegprot = 0.35 h⁻¹) in nondividing cells. (D) Dose of 100 nM siRNA every 7 days with a target protein half-life of 48 h (kdegprot =0.014 h⁻¹) in nondividing cells. (E) Effect of variations in cell doubling time and target protein half-life on the ability to maintain a target protein level below a threshold of 50% its pre-treatment value over the 25-day period. I, 100 nM (day 0); II, 100 nM (days 0, 7, 14); III, 100 nM (days 0, 3, 7, 10, 14, 17, 21, 24). Surface vertices represent the fraction of the total time during which the relative protein level is below the 50% threshold.