Gene therapy of x-linked adrenoleukodystrophy using hematopoietic stem cells and a lentiviral vector

X-linked adrenoleukodystrophy (ALD) is a severe demyelinating disease of the brain caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette (ABC) transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We have developed a gene therapy strategy based on ABCD1 gene transfer to autologous hematopoietic stem cells (CD34+) by a lentiviral vector derived from HIV-1. We initiated a clinical trial involving three ALD patients for whom no matched donor was available. Autologous CD34+ cells were transduced ex vivo with an HIV derived vector the wild-type ABCD1 gene then re-infused after myeloablative treatment. Polyclonal reconstitution was detected up to 24 to 30 months, with between 9 % and 14 % of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein, strongly suggesting that the patients' hematopoietic stem cells have been successfidly transduced Cerebral demyelination halted after 14 to 16 months in two first treated patients an outcome similar to that achieved by allogeneic HCT. These results suggest that lentiviral vectors are suitable fur transferring therapeutic genes to hematopoietic stem cells, and provide the first example of successful gene therapy for a severe neurodegenerative disease.