Project

The European research project CureCN sought to develop a curative gene therapy against the ultra-rare Crigler-Najjar syndrome (CN). Crigler-Najjar is a life-threatening liver disease which affects one in a million individuals at birth. The goal of the CureCN consortium was thus to prove the safety and efficacy of an adeno-associated virus (AVV) gene therapy in a clinical trial and make it available to patients.

About Crigler-Najjar

The inherited Crigler-Najjar syndrome occurs directly after birth. It is 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 a liver transplant that implies high risks of complications.

Treatment with phototherapy – a treatment with blue light – reduces symptoms, but is very debilitating as it requires 10 to 14 hours therapy per day. Furthermore, it loses its efficiency over time so that all patients depend upon a liver transplant in the long term. On the other hand, phototherapy does not eliminate the risk of life-threatening spikes of bilirubin. The lack of a permanent curative treatment of CN results in a shortened life expectancy of the affected patients.

Main Goals within CureCN

Partners in CureCN were chosen for their complementary scientific excellence, technical expertise, and experience in translational research. Together, they took on the mission to find a curative treatment for CN syndrome. The project’s major goals were:

• Developing a curative AAV gene therapy and validating a technology transposable to many other inherited liver-related disorders
• Proving the safety and efficacy of the vector-mediated gene transfer with AAV in a clinical trial
• Providing a treatment suitable for very young CN patients as well as for older patients with a pre-existing immunity to AAV
• Verifying a way to eradicate pre-existing immunity to AAV
• Accelerating the orphan drug development towards a marketing authorisation for the treatment

Another important goal was to establish the first global Crigler-Najjar patient registry. Overall, CureCN set out to provide better information for patients, families, healthcare providers and the general public about CN syndrome and existing treatments.

project leaflet

A leaflet summarizing the main details of the CureCN project is available for download in 3 languages:

English French Italian

Publications

2019

• Preclinical Development of an AAV8-hUGT1A1 Vector for the Treatment of Crigler-Najjar Syndrome
  Fanny Collaud, Giulia Bortolussi, Laurence Guianvarc’h, Sem J. Aronson, Thierry Bordet, Philippe Veron, Severine Charles, Patrice Vidal, Marcelo Simon Sola, Stephanie Rundwasser, Delphine G. Dufour, Florence Lacoste, Cyril Luc, Laetitia v. Wittenberghe, Samia Martin, Christine Le Bec, Piter J. Bosma, Andres F. Muro, Giuseppe Ronzitti, Matthias Hebben, Federico Mingozzi
• Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in the Context of Gene Therapy for Crigler–Najjar Syndrome
  Sem J. Aronson, Philippe Veron, Fanny Collaud, Aurélie Hubert, Virginie Delahais, Géraldine Honnet, Robert J. de Knegt, Norman Junge, Ulrich Baumann, Angelo Di Giorgio, Lorenzo D'Antiga, Virginia M. Ginocchio, Nicola Brunetti-Pierri, Philippe Labrune, Ulrich Beuers, Piter J. Bosma, Federico Mingozzi

2020

• A Quantitative In Vitro Potency Assay for Adeno-Associated Virus Vectors Encoding for the UGT1A1 Transgene
  Sem J. Aronson, Robert S. Bakker, Sascha Moenis, Remco van Dijk, Giulia Bortolussi, Fanny Collaud, Xiaoxia Shi, Suzanne Duijst, Lysbeth ten Bloemendaal, Giuseppe Ronzitti, Andrés F. Muro, Federico Mingozzi, Ulrich Beuers, Piter J. Bosma
• Capsid-specific removal of circulating antibodies to adeno-associated virus vectors
  Berangere Bertin, Philippe Veron, Christian Leborgne, Jack-Yves Deschamps, Sophie Moullec, Yves Fromes, Fanny Collaud, Sylvie Boutin, Virginie Latournerie, Laetitia van Wittenberghe, Benoit Delache, Roger Le Grand, Nathalie Dereuddre-Bosquet, Olivier Benveniste, Philippe Moullier, Carole Masurier, Otto Merten, Federico Mingozzi

2022

• Disease burden and management of Crigler-Najjar syndrome: Report of a world registry
  Sem J Aronson, Norman Junge, Mediha Trabelsi, Wided Kelmemi, Aurelie Hubert, Karlla W Brigatti, Michael D Fox, Robert J de Knegt, Johanna C Escher, Virginia M Ginocchio, Raffaele Iorio, Yan Zhu, Figen Özçay, Fakher Rahim, Mortada H F El-Shabrawi, Eyal Shteyer, Angelo Di Giorgio, Lorenzo D'Antiga, Federico Mingozzi, Nicola Brunetti-Pierri, Kevin A Strauss, Philippe Labrune,Ridha Mrad,Ulrich Baumann, Ulrich Beuers, Piter J Bosma, CureCN Consortium

2023

• Analysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation
  Elena Piletska, Philippe Veron, Bérangère Bertin, Federico Mingozzi, Donald Jones, Rachel L. Norman, Joseph Earley, Kal Karim, Alvaro Garcia-Cruz, Sergey Piletsky
• Gene Therapy in Patients with the Crigler–Najjar Syndrome
  Lorenzo D’Antiga, Ulrich Beuers, Giuseppe Ronzitti, Nicola Brunetti-Pierri, Ulrich Baumann, Angelo Di Giorgio, Sem Aronson, Aurelie Hubert, Roberta Romano, Norman Junge, Piter Bosma, Giulia Bortolussi, Andrés F. Muro, Ravaka F. Soumoudronga, Philippe Veron, Fanny Collaud, Nathalie Knuchel-Legendre, Philippe Labrune, and Federico Mingozzi