Crigler-Najjar syndrome affects about one in a million people at birth.
Because of a defective gene, these individuals lack an essential enzyme in their liver to eliminate bilirubin, a toxic bile pigment that accumulates in all body tissues causing jaundice and potentially leading to irreversible and lethal neurological damage.
Researchers from the EU-funded CURECN project are studying that defective gene, known as UGT1A1, and developing and testing novel gene therapy techniques to safely replace it with a healthy copy. The goal is to restore normal liver function and effectively cure Crigler-Najjar syndrome.
'Although extremely rare, the healthcare, financial and emotional burden of CN syndrome is very high. The lack of a permanent cure for the disease results in a shortened life expectancy and an impaired quality of life for individuals suffering from this genetic disease,' says Federico Mingozzi, CURECN project coordinator and head of the Immunology and Liver Gene Therapy team at the non-profit Genethon research institute in France.
'The CURECN project is therefore expected to bring significant benefits to patients and decrease the socioeconomic burden of the syndrome.'
An alternative to liver transplants
The CURECN approach uses an innocuous adeno-associated virus (AAV) as a carrier to deliver corrective genetic information into the body. Adeno-associated viruses, which are infectious to humans but are not known to have harmful effects, are currently the vectors of choice for many emerging gene therapy treatments.
They have previously been used in promising human trials of liver gene transfer therapies to treat hemophilia and eye gene transfer to treat congenital blindness.
The CURECN partners have designed an optimized AAV vector to safely target liver cells with a healthy copy of the defective gene responsible for CN. Having shown promising results in preclinical trials, the project has now launched a human trial involving 17 Crigler-Najjar patients at four medical centers in Europe.
'Our goal is to prove the therapy's safety and efficacy in the clinical trials, eventually paving the way for regulatory approval and the commercialization of a cure for Crigler-Najjar patients, hopefully allowing them to live normal lives free of symptoms,' says Fanny Collaud, the project's deputy team leader.
At present, the only way to control the symptoms of Crigler-Najjar requires patients to undergo prolonged phototherapy sessions in which they are subjected to special wavelengths of blue light for up to 10 or 12 hours a day to reduce bilirubin levels. The only cure is a liver transplant, a costly and risky procedure with long-term side effects, requiring patients to take immunosuppressive drugs for life in order to prevent their immune system rejecting the new liver.
Gene therapy faces a similar immunosuppressive challenge, although only for a limited period of time around vector administration, as patients can develop sustained antibody responses to AAV vectors. The CURECN consortium is therefore developing novel technologies to suppress immune responses and remove pre-existing antibodies.
This will allow the treatment to be administered to patients who have previously built up immunity to AAV, or to re-administer gene therapy to previously treated patients if needed to achieve long-term efficacy.
'Innovations derived from CURECN studies will have a major impact on the development of all AAV vector-based gene therapies for inherited diseases, particularly other forms of metabolic liver diseases,' Collaud says.
'Liver gene transfer therapy has the potential to reduce the hospitalization and treatment burden for many diseases, many of which affect children; reduce complications and morbidity associated with current treatments; and potentially provide an alternative to liver transplantation.'