Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive marrow failure.
Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential
cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair
enzymes . However, the collection of hCD34+-cells in FA patients implies particular challenges because
of the reduced numbers of progenitor cells present in their bone marrow (BM)  or mobilized
peripheral blood [3-5]. In addition, the FA genetic defect fragilizes the HSCs . These particular features
might explain why the first clinical trials using murine leukemia virus derived retroviral vectors
conducted for FA failed to show engraftment of corrected cells. The gene therapy field is now moving
towards the use of lentiviral vectors (LVs) evidenced by recent succesful clinical trials for the treatment
of patients suffering from adrenoleukodystrophy (ALD) , β-thalassemia , metachromatic leukodystrophy
 and Wiskott-Aldrich syndrome . LV trials for X-linked severe combined immunodificiency
and Fanconi anemia (FA) defects were recently initiated [11, 12]. Fifteen years of preclinical
studies using different FA mouse models and in vitro research allowed us to find the weak points in
the in vitro culture and transduction conditions, which most probably led to the initial failure of FA
HSC gene therapy. In this review, we will focus on the different obstacles, unique to FA gene therapy,
and how they have been overcome through the development of optimized protocols for FA HSC culture
and transduction and the engineering of new gene transfer tools for FA HSCs. These combined advances
in the field hopefully will allow the correction of the FA hematological defect in the near future.
Keywords: Fanconi anemia, Hematopoietic stem cell, Lentiviral vector, Gene therapy, Targeted cell transduction, Pseudotyping,
Reactive oxygen species, Bone marrow failure.
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