Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome

ABSTRACT

Introduction: The Crigler–Najjar syndrome (CNS) is an ultra-rare recessive disorder of the liver. There is no effective cure, except for liver transplantation, a procedure with many risks and shortcomings. Thus, the development of novel therapeutic approaches is a clinical need.

Areas covered: This review aims at describing potentialities and limitations of novel experimental treatments that can be applied to cure the CNS and other metabolic liver diseases. These include pharmacological and gene therapy approaches, some of them are now being applied in clinical trials of Crigler–Najjar patients. Brief descriptions of bilirubin metabolism, mechanisms of disease, and animal models are also included.

Expert opinion: AAV-mediated gene therapy approaches to pediatric liver diseases are very challenging due to the potential loss of viral DNA consequent to liver growth. Novel immunomodulatory strategies are being developed that can allow re-administration of the therapeutic vector by blocking the generation of anti-AAV neutralizing antibodies. Another very promising approach is gene targeting of the therapeutic cDNA into a ‘safe-harbor locus,’ resulting in the permanent correction of the genetic defect. However, further experimentation is still required to increase safety and efficacy. The success of these approaches will result in alternative therapies to liver transplantation.

KEYWORDS:

• Kernicterus
• phototherapy
• bilirubin-induced neuro-inflammation
• AAV-mediated liver gene therapy
• genome editing

Article highlights

• The development of novel therapies for the CNS type I is a clinical need. PT is effective temporarily and there is no definitive cure except for liver transplantation, a procedure with many shortcomings and risks.

• The availability of mouse models bearing Ugt1 null mutations with phenotypes closely mimicking the human syndrome improved significantly the understanding of the disease and paved the way to explore new therapeutic approaches

• AAV-mediated gene therapy emerged as a valuable option for adult patients, but still faces potential limitations in pediatric and juvenile patients due to the possibility of vector dilution in a growing liver.

• Immunomodulatory approaches blocking the generation of neutralizing anti-AAV antibodies consequent to the first treatment are being tested. These approaches will allow re-administration of the therapeutic AAV vector in the case of loss of efficacy.

Genome editing and targeted genome integration are very promising alternative approaches that result in the permanent modification of the genome, overcoming AAV vector dilution in pediatric subjects and ensuring long-lasting correction of the genetic defect.This box summarizes key points contained in the article.

Declaration of interest

A Muro has received ICGEB Intramural funds and financial support from Beneficentia Stiftung (BEN 2015/67). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by Beneficentia Stiftung, Vaduz, Lichtenstein (BEN 2015/67).