Liver-targeting gene therapy cures cholestasis in micePublished: April 9, 2019
Researchers provide preclinical evidence for the potential of adeno-associated virus 8 (AAV8)-mediated gene therapy 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 the Journal of Hepatology, Dr Piter Bosma and team at the Amsterdam University Medical Center tested whether AAV-mediated gene therapy targeting the liver could correct ABCB4 deficiency and prevent liver injury in Abcb4 -/- mice.
To do this, the team injected a single dose of AAV8-hABCB4 under control of a liver specific promoter into the tail of 10 weeks old Abcb4-/- mice. Animals were sacrificed either 10 or 26 weeks after injection to assess transgene persistence. Biliary phospholipids and liver fibrosis were then assessed.
Results showed that the transgene was stably expressed in all animals up to 26 weeks after administering AAV8-hABCB4. Biliary phospholipid excretion was restored to levels that could ameliorate liver damage. This prevented progressive liver fibrosis and reduced hepatocyte proliferation for the entire duration of the study.
Findings from the study provide preclinical evidence for the use of a single dose of AAV8-hABCB4 in correcting the disease in Abcb4 -/- mice. Further studies are required to test whether AAV-mediated gene therapy approach could be an option in PFIC3 patients.
Source: Liver-directed gene therapy results in long term correction of progressive familial intrahepatic cholestasis type 3 in mice. Aronson SJ et al., Journal of Hepatology. DOI