Liver Biopsy Following Gene Therapy For Hemophilia

Not yet recruiting

• Conditions: Hemophilia A; Hemophilia B
• Interventions: Procedure: Liver Biopsy

• Registration Number: NCT05932914
• Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary

This observational study will obtain liver biopsy samples and evaluate the long-term effect of adeno-associated virus (AAV)-mediated gene therapy on the liver tissue in adult patients with hemophilia A or hemophilia B who have previously been treated with a factor VIII or factor IX gene-containing AAV-vector for liver-targeted gene transfer. Participants are from a cohort of patients treated with AAV-mediated gene transfer and at least 6 months after vector infusion.

Detailed Description

To better understand the effect of AAV-mediated gene transfer on the liver, eligible participants will have a one-time, standard transjugular liver biopsy (TJLB) under moderate sedation. Or, no intervention if prior liver biopsy tissue is available.

Participants are from a cohort of patients treated with AAV-mediated gene transfer and at least 6 months after vector infusion expressing at least 1% of FVIII or FIX activity, respectively.

Evaluations will be done on the liver tissue samples regarding transduction frequency, morphology, gene expression patterns, vector genome integrations, epigenetic signature, and consequences of transgene expression on hepatocytes.

Study Timeline

• Study First Submitted: 2023-06-27
• Study First Submitted QC: 2023-06-27
• Study First Posted: 2023-07-06
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-15
• Last Update Posted: 2025-04-18
• Study Start: 2025-05
• Primary Completion: 2026-05
• Study Completion: 2026-05

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Male
• Target Recruitment: 8

Inclusion Criteria

• Age ≥18 to 80 years

• Patients, who were enrolled and treated in one of the following clinical trials:

  • AGT4HB (EudraCT number: 2005-005711-17; NCT00979238) - FIX AAV gene therapy trial (sponsor: St. Jude Children's Research Hospital)
  • GO8 (EudraCT number:2016-000925; NCT03001830) - FVIII AAV gene therapy trial (sponsor: University College, London)

• Patients with endogenous expression of FVIII/FIX at >1% after gene transfer that is stably maintained for more than six months after vector infusion

• Able to give informed consent

• Able to comply with study requirements

Exclusion Criteria

• Any condition that, in the opinion of the investigator or sponsor of the ongoing clinical trial in which the patient is participating in, would prevent the patient from fully complying with the requirements of the clinical trial and/or would influence or interfere with evaluation and interpretation of subject safety or efficacy result of that ongoing clinical trial
• Platelet count <100x10^9/L
• INR >1.5
• Abnormal kidney function with estimated GFR <50 mL/min (calculated using the CKD-EPI equation)
• Known allergy to iodine-based intravenous contrast agents
• Known allergy to local or general anesthetics
• Known allergic reaction to FVIII/FIX concentrate infusions
• Presence of FVIII/FIX inhibitor
• Evidence of any bleeding disorder other than hemophilia A or B

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Participants	Liver Biopsy	Those who meet the Eligibility Criteria

Primary Outcome Measures

Name	Time	Method
Assessment of the number of hepatocytes transduced with AAV vector genome in liver biopsy samples analyzed by FISH	single time point (day of biopsy)	Fluorescence in situ hybridization (FISH)

Secondary Outcome Measures

Name	Time	Method
The degree of hepatocyte damage at a morphological level	single time point (day of biopsy)	Standard and immunohistochemical tissue staining
The number of hepatocytes revealing FVIII/FIX RNA in-situ transcripts	single time point (day of biopsy)	Assessment of RNA in-situ transcripts
The number and types of epigenetic changes within the AAV genome in the liver	single time point (day of biopsy)	DNA methylation analysis and histone association studies
The qualitative and quantitative assessment of the RNA transcriptome	single time point (day of biopsy)	Assessment of RNA transcriptome
The number and type of hot spots for integration of AAV provirus in liver cells	single time point (day of biopsy)	DNA sequencing

Trial Locations

Locations (1)

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States