Liver Biopsy In Haemophilia Gene Therapy

Study Overview
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Brief Summary
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To perform a liver biopsy in haemophilia A and B patients stably expressing human FVIII/FIX for a period of at least 6 months following AAV mediated gene transfer. This is to obtain tissue for analysis, to understand if FIX/FVIII transgenic protein expression is mediated by AAV proviral DNA that is integrated into the host cell DNA or if stable expression in humans is mediated by episomal maintained AAV genome.

Detailed Description
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To better understand the consequences of AAV gene transfer patients will be recruited to undergo a liver biopsy. Patients will be from a unique cohort of successfully treated patients, who are at least 6 months post gene transfer (patients will be at varying timepoints post gene transfer, with the current maximum time post gene transfer being 9.5 years) and have been treated with self-complementary and over-sized AAV vectors will advance the state-of-the-art, in the following aspects: Provide a clearer insight into the AAV life cycle in human liver Define the number of human hepatocytes that are transduced Improve our understanding at the human hepatocyte level of long-term consequences of AAV mediated transgene expression from the liver that will include (i) changes in the pattern of gene expression in human hepatocytes following AAV mediated gene transfer, (ii) information on the epigenetic signature in the liver following AAV mediated gene transfer and how this changes with time and (iii) the consequences of transgene expression in hepatocytes including the endoplasmic reticulum stress response This study will provide new data addressing several unknowns with AAV mediated gene transfer in humans that will better inform on safety and efficacy following AAV gene transfer for patients who have already participated in gene therapy studies as well as those considering this treatment option.

Official Title
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Liver Biopsy In Haemophilia Gene Therapy

Conditions
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Hemophilia B, Severe, Hemophilia A, Severe

Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and aged 18 to 80 years old Patients who were enrolled and treated in one of the following clinical trials: AGT4HB (EudraCT No 2005-005711-17) - FIX AAV gene therapy trial (Sponsor: St Jude Children's Research Hospital) GO-8 (EudraCT No 2016-000925-38) - FVIII AAV gene therapy trial (Sponsor: UCL) FLT180a-01 (EudraCT: 2017-000852-24) - FIX AAV gene therapy trial ((Sponsor: UCL) Patients with endogenous FVIII:C/FIX:C expression at >1% after gene transfer that is stably maintained for >6 months and associated with normal prothrombin (PT) and thrombin times (TT) as determined in a coagulation assay Exclusion Criteria: Patients with a platelet count measured at <140 x109/L Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study and/or would influence or interfere with evaluation and interpretation of subject safety or efficacy result. Patients with abnormal kidney function (estimated GFR <50ml/min) Patients with a known allergy to iodine-based intravenous contrast agents Patients with a known allergy to local or general anaesthetic Patients with a known reaction to FVIII/FIX concentrate infusions Presence of FVIII or FIX inhibitor (done within 14 weeks of biopsy) Evidence of any bleeding disorder not related to haemophilia A or B Patients unable and unwilling to provide and sign an informed consent.

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

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Liver Biopsy<br>All patients undergo a liver biopsy only | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comprehensive analysis of AAV integration frequency in hepatocytes | Comprehensive analysis of AAV integration frequency in hepatocytes | single time point (day of biopsy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The degree of hepatocyte damage at a morphological level | The degree of hepatocyte damage at a morphological level | single time point (day of biopsy) |