Fanconi anemia ( FA ) is a complex genetic disease associated with congenital abnormalities, bone marrow failure ( BMF ) and cancer predisposition.
Allogeneic transplantation constitutes the preferential treatment of the BMF that takes place in most Fanconi anemia patients.
Researchers have recently proposed a gene therapy approach of Fanconi anemia group A gene ( FA-A ) patients with lentiviral vectors. In a first step, a therapeutic lentiviral vector expressing FANCA under the regulation of the PGK promoter was generated ( PGK-FANCA-WPre* LV ).
The short incubation ( less than 36 h ) of purified CD34+ cells from FA-A patients with a pre-GMP FA-LV produced by Genethon facilitated the transduction of 32-85% of these progenitor cells, and efficiently reverted their characteristic hypersensitivity to DNA cross-linking drugs.
To test the safety of this vector, Lin- BMCs from Fanca-/- mice were transduced overnight with the FA-LV and transplanted into irradiated Fanca-/- recipients.
Insertion site analyses showed a safe and policlonal pattern of hematopoietic repopulation both in primary and secondary recipients, consistent with the absence of any myelodisplasia or leukemia produced by insertional oncogenesis.
To facilitate the collection of a significant number of CD34+ cells in the clinical trial, Fanconi anemia patients will be treated both with G-SCF and with an antagonist of the CXCR4 receptor, Plerixafor ( Mozobil ).
Mobilized CD34+ cells will then be cryopreserved until the development of the BMF in the patient, or directly transduced and re-infused in Fanconi anemia patients with BMF signs. ( Xagena )
Bueren JA, Human Gene Therapy, 2013