Treatment for severe Crigler-Najjar syndrome using gene therapy

An Open-label, Phase 2 Trial to Evaluate the Efficacy and Safety of a Single Intravenous Administration of GNT0003 (an Adeno-associated Viral (AAV) Vector Expressing the UGT1A1 Transgene) Following Imlifidase Pre-treatment in Adult Participants With Severe Crigler-Najjar Syndrome (CNS) Requiring Daily Phototherapy and Presenting Pre-existing Anti-AAV8 Antibodies

This study is testing a new gene therapy to see if it can safely lower bilirubin levels in people with severe Crigler-Najjar syndrome and help them avoid needing a liver transplant.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 3 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Genethon (other)
• Locations: 1 site (Clamart)
• Trial ID: NCT06518005 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the efficacy and safety of GNT0003, a gene therapy designed to correct the genetic defect in patients with severe Crigler-Najjar syndrome, following pre-treatment with Imlifidase to allow access for those with pre-existing antibodies. The trial aims to reduce the accumulation of neurotoxic unconjugated bilirubin by providing a functional copy of the UGT1A1 gene through a recombinant viral vector. Participants will be monitored for safety and effectiveness in reducing bilirubin levels, with the goal of improving patient outcomes without the need for liver transplantation.

Who should consider this trial

Good fit: Ideal candidates are individuals with severe Crigler-Najjar syndrome requiring extensive phototherapy and confirmed mutations in the UGT1A1 gene.

Not a fit: Patients who have undergone liver transplantation or have significant underlying liver disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a curative option for patients with severe Crigler-Najjar syndrome, significantly improving their quality of life.

How similar studies have performed: While gene therapy approaches for genetic disorders are being explored, this specific application for Crigler-Najjar syndrome is novel and has not been extensively tested in prior studies.

Eligibility criteria

Main Inclusion Criteria:

1. Severe Crigler-Najjar syndrome requiring ≥ 6 hours/ day of phototherapy
2. Molecular confirmation of mutation in the UGT1A1gene by DNA sequencing
3. Detectable serum neutralizing antibodies against AAV8
4. Laboratory parameters value not clinically significant
5. Highly effective method of contraception
6. Affiliated to or a beneficiary of a health care system

Exclusion Criteria:

1. Participation in another interventional trial within 6 months prior to start of clinical trial intervention and during the whole clinical trial
2. Fibrosis score ≥ 3 (METAVIR) or 10 kPa (FibroScan®)
3. Liver transplantation
4. Significant underlying liver disease, chronic hepatitis B, C and/or infected with Human immunodeficiency virus
5. Any other clinically significant illness
6. Uncontrolled hyperlipidemia.
7. History of major thrombotic events, active peripheral vascular disease, proven hypercoagulable conditions,
8. History or presence of thrombotic thrombocytopenic purpura (TTP) or known familial history of TTP
9. Prior or current treatment with Gene therapy, cell based therapy, CRISPR/Cas9 or any other form of gene editing, imlifidase

Where this trial is running

Clamart

• Hopital Antoine BECLERE — Clamart, France (RECRUITING)

Study contacts

• Principal investigator: Philippe LABRUNE, MD, PHD — APHP_Hopital Antoine BECLERE
• Study coordinator: GENETHON Clinical Development Department

Conditions: Crigler-Najjar Syndrome