Predictors of Hepatitis B Cure Using Gene Therapy to Deliver DNA Cleavage Enzymes: A Mathematical Modeling Approach
Figure 8
Packaging of multiple cleavage enzymes that target different HBV regions enhances potency and decreases resistance.
Simulation of HBV eradication employing gene therapy following a single dose. Each data point represents number of remaining infected cells (y-axis) after a simulation with one of 36 unique parameter sets. x-axis is functional multiplicity of infection (fMOI). Enzyme-DNA binding avidity is fixed (d = 0.04). Color represents number of enzymes delivered per vector (orange, green and blue = 1,2 & 3 respectively). Hill coefficient is 1, 2 and 5 (square, diamond and circle). The simulation assumes no pre-existing resistance. (a) Addition of multiple DNA cleavage enzymes within single vectors decreases the number of total remaining infected cells, particularly when vector delivery is high and intracellular binding cooperativity is present. (b) Addition of multiple DNA cleavage enzymes within single vectors decreases the number of total remaining infected cells harboring HBV cccDNA with any de novo resistance mutations, or (c) all possible resistance mutations. (d) Percentage of remaining infected cells containing totally resistant genomes following a single dose increases with high delivery, lower number of cleavage enzymes per vector, and higher binding cooperativity.