Clinical trial NCT05932914: Liver Biopsy Following Gene Therapy For Hemophilia
Official title: Liver Biopsy Following Gene Therapy For Hemophilia
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Hemophilia A
Hemophilia B
Keywords: AAV-mediated factor VIII (FVIII) gene transfer
AAV-mediated factor IX (FIX) gene transfer
Gene Therapy
Hemophilia A
Hemophilia B
Transjugular liver biopsy
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
First posted: 2023-07-06
Enrollment: 8
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Those who meet the Eligibility Criteria.

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.

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

Primary outcomes:
measure: Assessment of the number of hepatocytes transduced with AAV vector genome in liver biopsy samples analyzed by FISH
timeFrame: single time point (day of biopsy)
Secondary outcomes:
measure: The degree of hepatocyte damage at a morphological level
timeFrame: single time point (day of biopsy)
measure: The number and type of hot spots for integration of AAV provirus in liver cells
timeFrame: single time point (day of biopsy)
measure: The number of hepatocytes revealing FVIII/FIX RNA in-situ transcripts
timeFrame: single time point (day of biopsy)
measure: The number and types of epigenetic changes within the AAV genome in the liver
timeFrame: single time point (day of biopsy)
measure: The qualitative and quantitative assessment of the RNA transcriptome
timeFrame: single time point (day of biopsy)
Other outcomes:
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Ulrike Reiss, MD
role: PRINCIPAL_INVESTIGATOR
References: