ESPE Abstracts (2014) 82 PL4

Gene Therapy

P Aubourg

University Paris-Sud and INSERM, Le Kremlin-Bicêtre, Paris, France

Background: X-linked adrenoleukodystrophy (X-ALD) presents with two phenotypes: i) an adult form (adrenomyeloneuropathy, AMN), that involves axonal tracts without demyelination within the spinal cord and affects adult males and more than 80% of X-ALD heterozygote women in adulthood resulting in severe paraplegia. This far the most frequent form of X-ALD. Addison’s disease is very rare in X-ALD women but frequent in adult AMN males, very often with onset years or decades before neurologic symptoms appear. Importantly, 35% of AMN males develop cerebral demyelination which has the same poor prognosis as in X-ALD boys; ii) a childhood cerebral demyelinating form that affects boys between 4 and 12 years and leads to vegetative stage or death within few years. As in adult males with X-ALD, Addison’s disease precedes often the cerebral disease in boys. Whereas there is yet no treatment for AMN, allogeneic transplantation of normal hematopoietic stem cells (HCT) can arrest the progression of cerebral disease in boys and adult X-ALD males with good quality of life in long term, provided the procedure is performed at an early stage of cerebral disease. This emphasizes the crucial need to screen systematically all boys or adult males with Addison’s disease for X-ALD (measurement of VLCFA in plasma) and perform on a regular basis brain MRI in all X-ALD males with isolated Addison’s disease to detect early signs of cerebral demyelination.

Objective and hypotheses: Allogeneic HCT is not always possible due to lack of HLA-matched donor and remains associated with important mortality risks. It is the reason why autologous transplantation of hematopoietic stem cells (HSC) genetically corrected ex vivo with a lentiviral vector has been attempted in four boys with cerebral X-ALD.

Method: HSC gene therapy has been performed in four boys with cerebral X-ALD.

Results: Results with a follow-up of 4–7 years indicate similar efficacy than with allogeneic HCT with no complication due to the use of integrative viral vector and a phase III trial has recently been launched.

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