-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

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1022 Advances in the Gene Therapy of Patients with Fanconi AnemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Therapy and Transfer: Gene Therapy for Blood Cell Disorders
Hematology Disease Topics & Pathways:
Diseases, Biological, Therapies, Bone Marrow Failure, Biological Processes, Pediatric, gene therapy, DNA repair, Study Population, Clinically relevant, hematopoiesis, stem cells
Monday, December 3, 2018: 6:30 PM
Room 6B (San Diego Convention Center)

Juan A. Bueren1*, Susana Navarro, PhD1*, Wei Wang, PhD2*, Rebeca Sanchez-Dominguez, PhD1*, Eva Merino3*, Jose C Segovia, PhD1*, Anne Galy, PharmD, PhD4, María L. Lamana, MD, PhD1*, Rosa M Yañez, PhD5*, Jose A Casado, PhD1*, Yari A. Gimenez1*, Francisco J Roman-Rodriguez1*, Lara A. Alvarez1*, Roser Pujol, PhD6*, Jordi Surralles, PhD6*, Ricardo López, MD, PhD7*, Nagore García de Andoín, MD8*, Albert Catala, MD, PhD9*, Eva Galvez, MD3*, Raquel Hladun, MD10*, Jonathan D Schwartz, MD11, Manfred Schmidt, PhD12*, Cristina Díaz de Heredia, MD, PhD10*, Paula Rio, PhD1* and Julian Sevilla, MD, PhD3*

1Hematopoietic Innovative Therapies Division, CIEMAT/CIBERER/IIS. Fundación Jiménez Díaz, Madrid, Spain
2GeneWerk, Heidelberg, Germany
3Hospital Infantil Universitario Niño Jesus, FIB HIUNJ, CIBERER, Madrid, Spain
4Genethon, Evry, France
6Department of Genetics, Hospital de la Santa Creu i Sant Pau/ Autonoma University Barcelona/ CIBERER, Barcelona, Spain
7Hospital de Cruces, Bilbao, Spain
8Hospital Universitario de Donostia, Donostia, Spain
9Department of Hematology and Oncology, Hospital Sant Joan de D´eu, Barcelona, Spain
10Servei Oncologia i Hematologia Pediàtriques, Hospital Universitari Vall d’Hebron Vall d’Hebron, Barcelona, Spain
11Rocket Pharma, New York, NY
12GeneWerk GmbH, Heidelberg, Germany

Fanconi anemia (FA) is a DNA repair syndrome characterized by bone marrow failure, congenital abnormalities and cancer predisposition. Based on previous experimental results showing the in vivo proliferative advantage of gene corrected FA patients’ hematopoietic stem cells (HSCs; Rio, Navarro et al. Blood 2017) a gene therapy trial in non-conditioned FA-A patients was initiated in 2016. Six patients have been treated to-date using fresh and cryopreserved CD34+ cells mobilized to peripheral blood with G-CSF and plerixafor, and transduced with the PGK-FANCA.Wpre* lentiviral vector. Cell doses infused in four patients with a follow-up of at least 12 months varied from 0.6 to 1.4 million CD34+ cells/kg. Transduction efficacies of these samples, determined as vector copies per cell, ranged from 0.17 to 0.53 copies/cell. Despite the absence of patients’ conditioning, a marked in vivo expansion of gene-corrected cells was observed in all hematopoietic cell lineages analyzed in BM and PB. Significantly, up to 44% of corrected cells were determined in total PB cells at the most recent follow-up visit (24 month) in the first treated patient. Insertion site analyses in PB cells showed an oligoclonal pattern of hematopoietic reconstitution, and revealed engraftment of multipotent corrected HSCs and no evidence of insertion-site mediated clonal expansion. Functional studies showed significant increases in the resistance of BM progenitors to mitomycin C in all treated patients. Additionally, patients with higher levels of corrected cells also showed significant increases in the chromosomal stability of T cells exposed to diepoxybutane. Finally, analyses discriminating the presence of corrected and uncorrected PB cells in these patients showed marked increases in the total number of corrected leukocytes, contrasting to progressive decreases of uncorrected cells. Our studies demonstrate for the first time that lentiviral-mediated gene therapy results in progressive engraftment and phenotypic correction of HSCs in non-conditioned FA patients, suggesting that this gene therapy approach may constitute a low-toxicity option for the treatment and prevention of BMF in patients with FA.

Disclosures: Bueren: Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Navarro: Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Segovia: Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Casado: Rocket Pharmaceuticals Inc: Patents & Royalties. Schwartz: Rocket Pharmaceuticals: Employment, Equity Ownership. Schmidt: GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Rio: Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Sevilla: Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years ; Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties.

*signifies non-member of ASH