Hematopoietic Stem Cell Gene Therapy with Lentiviral Vector in X-Linked Adrenoleukodystrophy

Abstract 163^FN2

The most severe form of X-linked adrenoleukodystrophy (ALD) is characterized by rapidly progressive and lethal cerebral demyelination in childhood. The progression of cerebral demyelination of ALD can be arrested by allogeneic hematopoietic stem cell (HSC) transplantation (HCT) within 12–18 months, provided the procedure is performed at an early stage of the disease. The long term beneficial effects of HCT in ALD are likely due to the progressive turn-over of brain microglia that are derived from myeloid progenitors in the bone-marrow. Despite the increased availability of cord blood, not all boys with cerebral ALD and who are candidate for HCT have a suitable HLA-matched donor. In addition, allogeneic HCT remains associated with significant mortality risk. In late 2009, we reported that HSC gene therapy with lentiviral vector was able to arrest the progression of cerebral ALD in two boys who have no HLA-matched donor to perform HCT. ALD protein expression in myeloid and lymphoid lineages as well as the identification of identical lentiviral insertion sites in myeloid and lymphoid lineages strongly suggested that multi-potent long-term repopulating hematopoietic cells were transduced. In those 2 treated patients, hematopoiesis has remained polyclonal without evidence of clonal skewing or dominance up to the last follow-up. Data on clinical efficacy, gene marking and lentiviral integration studies with a longer follow-up (4 years ½) will be presented. HSC gene therapy however failed to arrest the progression of cerebral ALD in a third treated ALD patient, 36 months after gene therapy. Hematopoiesis remained also polyclonal in this patient and biological data that could explain failure of gene therapy in this patient will be presented. At last, data on a fourth patient who has been treated more recently (12 months) by HSC gene therapy will also be presented.