Changing the Natural History of Fanconi Anemia Complementation Group-A with Gene Therapy: Early Results of U.S. Phase I Study of Lentiviral-Mediated Ex-Vivo FANCA Gene Insertion in Human Stem and Progenitor Cells

• Published in: Blood 2019-11, Vol.134, p.3350-3350
• Main Authors: Czechowicz, Agnieszka, Roncarolo, Maria Grazia, Beard, Brian C, Law, Ken, Nicoletti, Eileen, Río, Paula, Bueren, Juan A., Schwartz, Jonathan D, Soni, Sandeep
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-127352

Background: Fanconi anemia (FA) is a rare genetic disorder characterized by defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. 80% of FA patients develop BMF. Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is a curative treatment for BMF, its utilization and efficacy is limited by availability of suitable human leukocyte antigen (HLA)-matched donors, risk of graft-versus-host disease (GVHD) and transplant-related toxicities. Ex-vivo insertion of a functional FANCA gene into autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) has been shown in preclinical studies to provide a survival advantage to the gene-modified stem cells, leading to correction of BMF. Feasibility of this approach was established in the FANCOLEN-1 clinical trial (Spain), although cell doses and transduction levels varied considerably. Modifications to the collection and manufacturing processes were made in the clinical studies to enhance the dose of transduced HSPCs, with the goal of preventing progression of BMF to obviate the need of an allo-HSCT. Design and Methods: RP-L102-0418 (clinicaltrials.gov # NCT03814408) is a U.S. Phase I clinical trial evaluating the feasibility and safety of autologous CD34+ cells transduced with a lentiviral vector (LV) carrying the FANCA gene (PGK-FANCA-WPRE) in two pediatric patients with FA-A. Patients 30/µL were eligible for treatment. Peripheral blood mononuclear cells were collected via leucocytapheresis on two consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and Plerixafor (Mozobil). CD34+ HSPCs were enriched, placed in culture with cytokines, and transduced with PGK-FANCA-WPRE LV. The investigational drug product (DP) (RP-L102) was infused fresh into patients within 4 hours of release, without any prior conditioning regimen. Patients are being followed for 3 years post-infusion for safety assessments (replication competent lentivirus (RCL), insertion site analysis (ISA)) and to ascertain early evidence of efficacy (increasing peripheral blood vector copy number (VCN) and BM mitomycin-C (MMC) resistance), along with stabilization/correction of cytopenias. Results: Two FA-A patients (aged 5 and 6 years) were consented and e