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Liver Biopsy Following Gene Therapy For Hemophilia

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ClinicalTrials.gov Identifier: NCT05932914
Recruitment Status : Not yet recruiting
First Posted : July 6, 2023
Last Update Posted : November 21, 2023
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Study Description
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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
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
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Study Type : Observational
Estimated Enrollment : 8 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Liver Biopsy Following Gene Therapy For Hemophilia
Estimated Study Start Date : December 2023
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : May 2025

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Participants
Those who meet the Eligibility Criteria
 Procedure: Liver Biopsy
Standard transjugular liver biopsy under moderate sedation


Outcome Measures
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Primary Outcome Measures :
  1. Assessment of the number of hepatocytes transduced with AAV vector genome in liver biopsy samples analyzed by FISH [ Time Frame: single time point (day of biopsy) ]
    Fluorescence in situ hybridization (FISH)


Secondary Outcome Measures :
  1. The degree of hepatocyte damage at a morphological level [ Time Frame: single time point (day of biopsy) ]
    Standard and immunohistochemical tissue staining

  2. The number and type of hot spots for integration of AAV provirus in liver cells [ Time Frame: single time point (day of biopsy) ]
    DNA sequencing

  3. The number of hepatocytes revealing FVIII/FIX RNA in-situ transcripts [ Time Frame: single time point (day of biopsy) ]
    Assessment of RNA in-situ transcripts

  4. The number and types of epigenetic changes within the AAV genome in the liver [ Time Frame: single time point (day of biopsy) ]
    DNA methylation analysis and histone association studies

  5. The qualitative and quantitative assessment of the RNA transcriptome [ Time Frame: single time point (day of biopsy) ]
    Assessment of RNA transcriptome


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Those who meet the Eligibility Criteria.
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05932914


Contacts
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Contact: Ulrike Reiss, MD 866-278-5833 referralinfo@stjude.org

Locations
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United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Contact: Ulrike Reiss, MD    866-278-5833    referralinfo@stjude.org   
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Ulrike Reiss, MD St. Jude Children's Research Hospital
More Information
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Additional Information:

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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT05932914    
Other Study ID Numbers: LIVBX
First Posted: July 6, 2023    Key Record Dates
Last Update Posted: November 21, 2023
Last Verified: November 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
AAV-mediated factor VIII (FVIII) gene transfer
AAV-mediated factor IX (FIX) gene transfer
Gene Therapy
 Hemophilia A
Hemophilia B
Transjugular liver biopsy
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
 Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked