Hemophilia A, Hemophilia B
Conditions
Keywords
AAV-mediated factor VIII (FVIII) gene transfer, AAV-mediated factor IX (FIX) gene transfer, Gene Therapy, Hemophilia A, Hemophilia B, Transjugular liver biopsy
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
This is a prospective cohort study evaluating the effect of AAV-mediated gene therapy on the liver in adult patients with hemophilia A or hemophilia B who have previously been treated with a FVIII/FIX gene-containing AAV-vector for liver-targeted gene transfer. To better understand the effect of AAV-mediated gene transfer on the liver, eligible participants can allow the use and analysis of already existing liver tissue samples, taken and preserved after having received gene therapy. Alternatively, eligible participants can consent to providing a new liver tissue sample which will be obtained by undergoing a standard transjugular liver biopsy (TJLB) procedure under moderate sedation. . The procedure will be done as outpatient (day 1) with post procedure follow-up on day 2, 3, 4 and 14.
Interventions
PROCEDURELiver Biopsy
Standard transjugular liver biopsy under moderate sedation
Sponsors
St. Jude Children's Research Hospital
Methodist University Hospital
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
MALE
Age
18 Years to 80 Years
Healthy volunteers
No
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:2014-003880-38; NCT02576795) - FVIII AAV gene therapy trial (sponsor: University College, London) * Able to give informed consent * Able to comply with study requirements
Exclusion criteria
(Do not apply to participants who will not undergo liver biopsy, and have leftover liver tissue from a previous biopsy procedure, because all
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Contacts
CONTACTUlrike Reiss, MD
PRINCIPAL_INVESTIGATORUlrike Reiss, MD
St. Jude Children's Research Hospital
Outcome results
None listed