The CureCN project, that ended on December 31st, 2023, aimed at the development of a curative gene therapy against the ultra-rare Crigler-Najjar syndrome (CN). CN is a life-threatening liver disease which affects one in a million individuals at birth caused by the deficiency of a liver-specific enzyme (uridine diphosphate Glucuronosyltransferase 1A1) that leads to the accumulation of toxic unconjugated bilirubin in all body tissues. Untreated, CN causes irreversible neurological damage in the brain and leads to death. The only curative treatment currently available is liver transplantation that implies high risks of complications.
Phototherapy – a treatment with blue light – reduces bilirubin levels, but it is very burdensome as it requires up to 14-hour therapy per day, loses efficacy over time and does not eliminate the risk of life-threatening spikes of bilirubin. CN patients depend upon a liver transplant in the long term as it represents the only curative treatment available. On the other hand, transplanted patients live under continue immunosuppression and are exposed to the risk of developing tumors, in particular melanoma. The lack of a curative treatment for CN results in a shortened life expectancy of the affected patients. The overall goal of the CureCN consortium was to prove the safety and efficacy of an adeno-associated virus (AAV) gene therapy in a clinical trial and make it available to patients.
The project’s main objectives were to:
-Develop a curative AAV gene therapy and validate a technology transposable to many other inherited liver-related disorders
-Prove the safety and efficacy of the vector-mediated gene transfer with AAV in a clinical trial
-Provide a treatment suitable for young CN patients as well as for older patients with a pre-existing immunity to AAV
-Identify a clinically ready method to eradicate pre-existing immunity to AAV
-Accelerate the orphan drug development towards marketing authorization
-Establish the first global CN patient registry to provide better information for patients, families, healthcare providers and the general public about CN syndrome and existing treatments.
At the end of the CureCN project, the clinical trial is in its pivotal phase, and first pediatric patients were dosed.A world CN registry of patients was created, data were collected all along the project from a pool of more than 200 patients and is still actively used by physicians all over the world, with the help of CN patients associations to make this registry known to patients. Some major pre-clinical work was also performed to determine the safety and efficacy of gene transfer in neonate and juvenile animals, to support the clinical study in pediatric patients. CureCN also aimed at addressing fundamental limiting issues associated pre-existing immunity to AAV. To this aim, some work was performed during the CureCN program to develop novel technologies for the modulation of antibody responses directed against AAV vectors through removal of pre-existing antibodies to AAV from the bloodstream.
