Predictors of Hepatitis B Cure Using Gene Therapy to Deliver DNA Cleavage Enzymes: A Mathematical Modeling Approach
Figure 7
Rapid development of de novo resistance to DNA cleavage enzyme therapy.
(a) Potent regimens with high fMOI (m*σ = 5), high enzyme – DNA binding avidity (d = 0.04), and positive binding cooperativity (h = 2) will allow for high levels of simulated resistance and predominance of resistant episomes following only 2 to 3 doses; a higher resistance rate (5% versus 1%) will promote a higher number of infected cells containing enzyme resistant episomes. (b) Infected cells containing enzyme resistant episomes will ultimately achieve equivalent levels assuming equal resistant rates whether a potent (m*σ = 5, d = 0.004 & h = 2) or less potent (m*σ = 1, d = 1 & h = 2) regimen is used. (c) If successive enzymes are dosed that target different regions within HBV cccDNA episomes, then the number of remaining episomes following multiple doses decreases accordingly; susceptible and resistant replication competent genomes are summed; by 60 days, all remaining episomes are resistant to each of the dosed enzymes (not shown in diagram).