Scientists at the University of Pennsylvania used adeno-associated viral (AAV) vector-mediated gene therapy in mice to rescue the lethal phenotype associated with Crigler-Najjar syndrome, an autosomal recessive disorder of bilirubin metabolism.
Crigler-Najjar syndrome is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene coding for uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) enzyme. Loss or partial absence of UGT1A1 enzyme activity results in toxic accumulation of bilirubin in the blood.
Newborns with Crigler-Najjar syndrome develops severe jaundice and the current medical management consists of phototherapy for atleast 12 hours a day. However, following puberty phototherapy becomes less effective and liver transplantation is the only cure to control the disease. Since AAV-mediated gene therapy has shown promise in treating liver-based monogenic diseases, the team led by Prof. James Wilson hypothesized that gene therapy could be used as a potential approach to reverse Crigler-Najjar syndrome.
In the study published in Human Gene Therapy, the team used UGT1 knockout (KO) mice models. UGT1 KO mice have been shown to display jaundice within eight hours of birth, and usually die seven days after birth. They administered the vector to these mice within 24 hours of birth via IV injection and followed the effects for one-year post vector administration to evaluate the duration of gene expression.
Results showed that high doses of AAV8 vector encoding human UGT1A1 under a liver-specific promoter protected UGT1 KO mice from lethal hyperbilirubinemia and rescued neonatal lethality in newborn UGT1 KO mice, extending its survival from 5 to 270 days post administration. Subsequent dose-ranging studies showed that even lower levels (3×109 genome copy/mouse) of the vector could prolong the survival of the UGT1 KO mouse to adulthood. Re-administration of the vector at a dose of 3×1012 genome copy/kg in adult UGT1 KO mice reduced the total serum bilirubin levels to wild-type level.
The study concludes that continuous expression of UGT1A1 through gene therapy would be a better option to control bilirubin levels than phototherapy. Additionally, re-administration of gene therapy later in adulthood is suggested as there are chances that the efficacy could be reduced following growth of liver over time. If re-administration of the vector is not desirable, administration of gene therapy to newborns could be used to increase the window of opportunity to find a donor liver.
Source: Greig JA et al., AAV8 Gene Therapy Rescues the Newborn Phenotype of a Mouse Model of Crigler-Najjar. Human Gene Therapy, February 2018. Reference