Liver Biopsy Following Gene Therapy For Hemophilia

Study Overview
=================
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.

Official Title
-----------------
Liver Biopsy Following Gene Therapy For Hemophilia

Conditions
-----------------
Hemophilia A, Hemophilia B

Intervention / Treatment
-----------------
* Procedure: Liver Biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants<br>Those who meet the Eligibility Criteria | Procedure: Liver Biopsy<br>* Standard transjugular liver biopsy under moderate sedation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the number of hepatocytes transduced with AAV vector genome in liver biopsy samples analyzed by FISH | Fluorescence in situ hybridization (FISH) | single time point (day of biopsy) | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AAV-mediated factor VIII (FVIII) gene transfer, AAV-mediated factor IX (FIX) gene transfer, Gene Therapy, Hemophilia A, Hemophilia B, Transjugular liver biopsy