Hybrid AAV-piggyBac gene therapy cures cholestasis in micePublished: May 30, 2019
Researchers provide preclinical evidence for the potential of a hybrid gene therapy strategy in treating a murine model of progressive familial intrahepatic cholestasis type 3 disease.
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe genetic liver disorder caused by ABCB4 deficiency. Depletion of ABCB4 protein results in impaired phospholipid transport into bile leading to cholestasis and progressive liver fibrosis. Currently there are no treatment options available and liver transplantation is the only possibility in end-stage liver disease.
In the present study published in Hepatology, Dr Ian Alexander and team at The University of Sydney and Sydney Children’s Hospitals Network developed a hybrid gene therapy strategy to correct ABCB4 deficiency and prevent liver injury in Abcb4-/- mice.
Using classical AAV-based gene therapy, the team observed significant reduction in vector transduction in adult Abcb4-/- mice with established liver disease, whereas high transduction was observed in disease-free normal mice and in homozygous juvenile mice prior to liver disease onset. However, delivery of predominantly non-integrating AAV vectors to juvenile mice resulted in loss of persistent transgene expression due to hepatocyte proliferation in the growing liver. This suggests AAV vector as not an ideal candidate for gene delivery in PFIC3.
To overcome this, a hybrid vector system was developed, which combined the high transduction efficiency of AAV vectors with somatic cell-integrating piggyBac transposons. This recombinant hybrid vector system was used to correct juvenile-onset chronic liver disease in a murine model of PFIC3. A single dose of hybrid vector at birth resulted in life-long restoration of bile composition, prevention of biliary cirrhosis and significant reduction in tumorigenesis.
Findings from the study provide preclinical evidence for the use of hybrid AAV-piggyBac transposons in delivering ABCB4 gene and correcting the disease in Abcb4-/-mice. According to the authors, the hybrid rAAV-piggyBac transposon vector strategy has the capacity to mediate lifelong phenotype correction and reduce tumorigenicity in PFIC3. Further studies are required to test whether this gene therapy approach could be clinically translated to PFIC3 patients.
Source: Prevention of cholestatic liver disease and reduced tumorigenicity in a murine model of PFIC type 3 using hybrid AAV-piggyBac gene therapy. Siew SM et al., Hepatology. DOI