The objective of this study is to assess the therapeutic safety and preliminary efficacy of a hematopoietic cell-based gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying the FANCA gene in subjects with Fanconi anemia subtype A (FA-A).

This is a pediatric open-label Phase 1 clinical trial and will include a safety evaluation and preliminary assessment of the efficacy of hematopoietic gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying the FANCA gene in subjects with FA-A. CD34+ cells will be transduced ex vivo with the therapeutic lentiviral vector and infused following transduction, without any prior conditioning. After transduction, product quality control evaluations will be carried out in aliquots of the transduced population. Investigational product will be infused via intravenous infusion with no upper or lower limit; a dose of ≥5 x 105 CD34+ cells/kg body weight will be considered optimal.

The active agent is a self-inactivating lentiviral vector carrying the therapeutic FANCA gene and the therapeutic product is subject's autologous HSCs that have been transduced with the lentiviral vector. The vector contains the functional FANCA gene.

Inclusion Criteria:

• Fanconi anemia, as diagnosed by chromosomal fragility assay of cultured T-lymphocytes in the presence of DEB or a similar DNA-crosslinking agent.

• Subjects of Fanconi Anemia complementation group A.

• Minimum age: 1 year and a minimum of 8 kg.

• Maximum age: 12 years.

• At least one of the following hematologic parameters below lower limits of normal:

  • Hemoglobin
  • Absolute neutrophils
  • Platelets

• At least 30 CD34+ cells/μL are determined in one BM aspiration within 3 months prior to initiation of CD34+ cell collection.

• If the number of C34+ cells/ μL in BM is in the range of 10-29, PB parameters should meet two of the three following criteria:

  • Hemoglobin: ≥11g/dL
  • Neutrophils: ≥900 cells/μL
  • Platelets: ≥60,000 cells/μL

• Provide informed consent in accordance with current legislation.

• Women of childbearing age must have a negative urine pregnancy test at the baseline visit and accept the use of an effective contraception method during participation in the trial.

Exclusion Criteria:

• Subjects with an available and medically eligible human leukocyte antigen (HLA)-identical sibling donor.

• Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities predictive of these conditions in BM aspirate analysis. This assessment should be made by valid studies conducted within the 3 months before the subject commences the stem cell mobilization/collection procedures of the clinical trial.

• Subjects with somatic mosaicism associated with stable or improved counts in all PB cell lineages. (If T-lymphocyte chromosomal fragility analysis indicates potential mosaicism, a medically significant decrease in at least one blood lineage over time must be documented to enable eligibility).

• Lansky performance status ≤60%.

• Any concomitant disease or condition that, in the opinion of the Principal Investigator, renders the subject unfit to participate in the study.

• Pre-existing sensory or motor impairment ≥grade 2 according to the NCI CTCAE v5.0 criteria.

• Pregnant or breastfeeding women.

• Hepatic dysfunction as defined by either:

  • Bilirubin >3.0 × upper limit of normal (ULN) or
  • Alanine aminotransferase (ALT) > 5.0 × ULN or
  • Aspartate aminotransferase (AST) > 5.0 × ULN

• Renal dysfunction requiring either hemodialysis or peritoneal dialysis.

• Pulmonary dysfunction as defined by either:

  • Need for supplemental oxygen during the prior 2 weeks in absence of acute infection.
  • Oxygen saturation by pulse oximetry <90%.

• Evidence of active metastatic or locoregionally advanced malignancy for which survival is anticipated to be less than 3 years.

• Subject is receiving androgens (i.e. danazol, oxymethalone).