New diagnostic and therapeutic approaches for the Crigler-Najjar Syndrome Type I

The Crigler-Najjar Syndrome Type I is a rare disease (incidence around 1/1000000 births) associated with a complete hepatic deficit of bilirubin glucuronosyltransferase activity. Bilirubin is the breakdown product of heme groups, present in hemoglobin in red cells and myoglobin in muscle. Principally produced in spleen, bilirubin is conjugated in the liver. Unconjugated bilirubin may be neurotoxic. The CNI disease is caused by a mutation in the gene that encodes for the only liver enzyme that allowing bilirubin conjugation and its removal in the bile fluid. The disease becomes apparent during the neonatal period by early, intense jaundice due to unconjugated bilirubin. There is no permanent cure for the disease, with lifelong risk of Bilirubin Encephalopathy (kernicterus), producing serious neurological damage leading to death if untreated. At present, CN patients are temporarily treated with 10-12 hours of daily phototherapy. However, the effectiveness of phototherapy is reduced with the age and the only effective therapy is liver transplantation. However, transplantation is possible only in a restricted number of cases and is associated with significant morbidity and mortality. It generally requires lifelong immunosuppression to prevent organ rejection and involves substantial risks and costs. In the present project we propose to establish new diagnostic and therapeutic approaches to improve the early detection of neuronal damage due to Bilirubin Encephalopaty and its prevention, and to pave the way towards a permanent correction of the genetic defects present in Crigler-Najjar Syndrome Type I patients by establishing a long-lasting AAV-mediated gene therapy to correct the genetic defect in mice. We look forward to using the developed vectors and protocols to improve the condition of patients, by offering them a therapeutic alternative other than liver transplantation as the only available permanent treatment.