2) Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia.

Abstract

Fanconi anemia (FA) is a DNA repair syndrome generated

by mutations in any of the 22 FA genes discovered to

date1,2. Mutations in FANCA account for more than 60% of

FA cases worldwide3,4. Clinically, FA is associated with congenital

abnormalities and cancer predisposition. However,

bone marrow failure is the primary pathological feature of FA

that becomes evident in 70–80% of patients with FA during

the first decade of life5,6. In this clinical study (ClinicalTrials.

gov, NCT03157804; European Clinical Trials Database, 2011-

006100-12), we demonstrate that lentiviral-mediated hematopoietic

gene therapy reproducibly confers engraftment

and proliferation advantages of gene-corrected hematopoietic

stem cells (HSCs) in non-conditioned patients with FA

subtype A. Insertion-site analyses revealed the multipotent

nature of corrected HSCs and showed that the repopulation

advantage of these cells was not due to genotoxic integrations

of the therapeutic provirus. Phenotypic correction of blood

and bone marrow cells was shown by the acquired resistance

of hematopoietic progenitors and T lymphocytes to DNA

cross-linking agents. Additionally, an arrest of bone marrow

failure progression was observed in patients with the highest

levels of gene marking. The progressive engraftment of corrected

HSCs in non-conditioned patients with FA supports

that gene therapy should constitute an innovative low-toxicity

therapeutic option for this life-threatening disorder.