Crigler-Najjar syndrome is a rare and serious disease caused by a deficiency in UDP-glycosyltransferase 1 polypeptide A1 (UGT1A1), a specific liver enzyme, leading to a potentially fatal build-up of free bilirubin in the serum and in all the body’s tissues, which can become toxic in the brain. GNT-0003 is in clinical trial for treatment of this disease.
What is Crigler-Najjar syndrome?
CN syndrome is a hereditary autosomal recessive disorder with an incidence of less than 1 case for 1 million people.
In CN syndrome, the malfunctioning of the process of bilirubin elimination from the bile mediated by the enzyme causes build-up of free bilirubin in the serum, which can become neurotoxic. Depending on the mutation of the gene, the severity of CN syndrome can vary from mild, with moderate increase in serum bilirubin rates, to severe, with high levels.
CN syndrome manifests in severe non-hemolytic jaundice, which develops during the first days of life, increases rapidly and continues thereafter. If not treated, patients with the highest levels of free bilirubin develop encephalopathy, leading to hypotonia, lethargy, deafness, mental retardation and eye movement paralysis. In patients with the most benign forms of CN, free bilirubin in the serum generally remains below toxic levels of bilirubinemia. However, irreversible neurological damage may occur due to sudden build-up of bilirubin due to trauma or septicemia.
To date there is no medication approved for treatment of CN syndrome. Phototherapy remains the gold standard for long-term treatment of patients with severe CN. Using phototherapy, the bilirubin rate has been able to be controlled for years in most young patients with severe CN. Up to 12 hours of phototherapy per day are required for patients with severe CN. Phototherapy is effective in reducing the bilirubin rate in children at the start of treatment, but later, patients still present a high risk for encephalopathy and neurological impacts which can be irreversible. The effectiveness of phototherapy can decrease gradually with age, requiring a longer period of phototherapy.
Prolonged phototherapy can have a major impact on a patient’s quality of life.
In the absence of alternative therapeutic options, orthotopic liver transplant is currently the only curative treatment for severe CN. Transplants present several limitations, such as the limited availability of donor livers, the need for immuno-suppression for the remainder of the patient’s life to prevent rejection, which can cause undesirable side effects (cancer, risk of viral infection), or the need for a repeat transplant. Patients and physicians are often reluctant to undertake such an irreversible procedure and seek out less invasive alternatives.
Restrictions related to quality of life and side effects from current treatments clearly highlight the benefit of new approaches such as gene therapy.
Crigler-Najjar syndrome: the role of Genethon and of the European CureCN consortium
Genethon’s main aim is to develop a curative treatment that restores the defective bilirubin-glucuronosyltransferase activity in the liver of patients suffering from CN.
Since 2013, Genethon has been developing a gene therapy treatment to treat patients with severe forms of CN syndrome by restoring expression of the UGT1A1 enzyme in the patient’s liver. Genethon has designed the product GNT 0003, conducted all the studies necessary for completing the clinical trial approval request and has developed the production process for the gene therapy vector.
An international clinical trial (NCT03466463) for which Genethon is the sponsor, for the product GNT 0003, kicked off in 2018 in France, the Netherlands and Italy.
This trial took place within the framework of a European consortium – CureCN – comprising 11 European partners from different sectors, including academia, hospital centers, companies and patient associations. Beyond the clinical trial, CureCN also aims to develop strategies to re-administer the gene therapy treatment by bypassing the immune response caused by the vectors.
Crigler-Najjar syndrome: what’s happening today?
The CareCN clinical trial is ongoing in the following hospitals: Antoine-Beclere hospital at Clamart (France, 92), ASST Papa Giovanni XXIII at Bergames (Italy), Azienda Ospedaliera Universitaria Federico II at Naples (Italy), AMC at Amsterdam (Netherlands).
The goal of CareCN is to evaluate tolerance to the product, assess its therapeutic effectiveness and the optimum dose.
Find out more
>> CureCN website
>> Videos on the project
- Ronzitti, G., et al., 2016, A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome, Molecular Therapy Methods and Clinical Development, 3: 16049.
- Collaud F, Bortolussi G, Guianvarc’h L, Aronson S, Bordet T, Veron P, Charles S, Vidal P, Sola M, Rundwasser S, Dufour D, Lacoste F, Luc C, Van Wittenberghe L, Martin S, Le Bec C, Bosma P, Muro A, Ronzitti G, Hebben M, and Mingozzi G, Preclinical development of an AAV8-hUGT1A1 vector for the treatment of Crigler-Najjar syndrome, Molecular Therapy Methods and Clinical Development, 2018 Dec 31;12:157-174.