Liver Biopsy Following Gene Therapy For Hemophilia

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05932914

Collaborator

(none)

Enrollment

Location

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A Hemophilia B	Procedure: Liver Biopsy

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 Design

Study Type:

Observational

Anticipated Enrollment :

8 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Liver Biopsy Following Gene Therapy For Hemophilia

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

May 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Participants Those who meet the Eligibility Criteria	Procedure: Liver Biopsy Standard transjugular liver biopsy under moderate sedation

Arm

Intervention/Treatment

Participants

Those who meet the Eligibility Criteria

Procedure: Liver Biopsy

Standard transjugular liver biopsy under moderate sedation

Outcome Measures

Primary Outcome Measures

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

The degree of hepatocyte damage at a morphological level [single time point (day of biopsy)]
Standard and immunohistochemical tissue staining
The number and type of hot spots for integration of AAV provirus in liver cells [single time point (day of biopsy)]
DNA sequencing
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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