Our previous studies have shown that hepatitis B virus (HBV) RNA interference (RNAi) can be effective at inhibiting HBV replication in mouse models. However, expression of too much RNAi can be toxic because it competes for the endogenous miRNA machinery. We use rational approaches to design more potent RNAi that functions at much lower doses. We are currently expressing this HBV RNAi from self-complementary adeno-associated virus serotype 8 (AAV8) vectors for testing in HBV transgenic mice.
Current treatments for HBV are effective in only ~50 % of patients. This is in part because of the persistence of the HBV DNA genome. We have set out to design the first class of drugs that directly target the genome of a DNA virus for destruction. We build designer restriction enzymes, called zinc-finger nucleases (ZFNs) , that specifically bind to HBV sequences and catalyze their cleavage in cells. We are currently testing this new type of therapeutic in mice.
MiRNAs (miRNAs) are small regulatory RNAs that modulate gene expression by binding to the 3’ untranslated regions of mRNAs and causing translational inhibition or mRNA degradation. The McCaffrey lab studies miRNAs involved in normal liver functions as well as miRNAs involved in pathological processes. We utilize mouse models and also obtain human clinical samples through collaborations with hepatologists and transplant surgeons here at the University of Iowa.