Predictors of Hepatitis B Cure Using Gene Therapy to Deliver DNA Cleavage Enzymes: A Mathematical Modeling Approach
Figure 6
High vector delivery, effective enzyme-HBV binding and cooperative binding predict effective cccDNA clearance.
All simulations of HBV eradication show results of ten weekly doses of therapy. A single enzyme is used and de novo resistance is ignored. (a) Each data point represents number of remaining infected cells (y-axis) after a simulation with one of 80 unique parameter sets. x-axis is functional multiplicity of infection (fMOI, separated by vertical black lines and not according to scale). Five different values for enzyme-DNA binding dissociation constant (d = 0.008, 0.04, 0.2, 1 & 5) are represented by blue, green, yellow, orange & red respectively; squares, diamonds, circles and triangles represent different values for the Hill coefficient (h = 0.5, 1, 2, 5). High fMOI, low binding dissociation constant and under conditions of moderate delivery and enzyme-DNA binding, high Hill coefficient (cooperative binding), predict high therapeutic potency. (b) Simulations of 10 weekly doses of a potent regimen (fMOI = 5.0, d = 0.04, h = 2, de novo resistance rate (Ψ) = 0) with decreasing fMOI following each dose due to humoral immunity. (σ: blue, green, orange and red represent decreases in fMOI with each dose of 90%, 50%, 10% and 0% respectively). Removal of vectors following each dose decreases effectiveness of therapy. (c & d) Simulations of 10 weekly doses of a potent regimen (fMOI = 5.0, d = 0.04, h = 2, de novo resistance rate (Ψ) = 0) assuming different burdens of infection (line color represents pre-therapy median number of HBV cccDNA molecules/cell) demonstrate relatively similar potency across highly variable densities of infection whether (c) infected cells or (d) total episomes are tracked as measures of therapeutic outcome.