Predictors of Hepatitis B Cure Using Gene Therapy to Deliver DNA Cleavage Enzymes: A Mathematical Modeling Approach
Figure 4
Theoretical effects of dosing multiple enzymes concurrently.
If two enzymes targeting separate sites are split among vectors, then “antagonistic potency” may occur: while the likelihood of de novo resistance decreases because fewer episomes are cleaved at only a single site, fewer episomes are targeted overall. “Synergistic potency” is more likely to occur if two enzymes are packaged within the same vector: intracellular dose of enzyme will double leading to fewer unbound episomes and lower probability of resistance due to higher overall binding of episomes at two sites. The possible therapeutic outcomes illustrated in the diagram are one of hundreds of potential outcomes given nine pre-therapy cccDNA molecules per cell, and are intended only as a demonstration of this principle.