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Science 6 November 2009:
Vol. 326. no. 5954, pp. 818 - 823
DOI: 10.1126/science.1171242
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Research Articles

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

Nathalie Cartier,1,2,* Salima Hacein-Bey-Abina,3,4,5,* Cynthia C. Bartholomae,6 Gabor Veres,7 Manfred Schmidt,6 Ina Kutschera,6 Michel Vidaud,1 Ulrich Abel,6 Liliane Dal-Cortivo,3,5 Laure Caccavelli,3,5 Nizar Mahlaoui,8 Véronique Kiermer,9 Denice Mittelstaedt,10 Céline Bellesme,2 Najiba Lahlou,11 François Lefrère,3 Stéphane Blanche,8 Muriel Audit,12 Emmanuel Payen,13,14 Philippe Leboulch,13,14,15 Bruno l’Homme,1 Pierre Bougnères,2 Christof Von Kalle,6 Alain Fischer,4,8 Marina Cavazzana-Calvo,3,4,5,* Patrick Aubourg1,2,*,{dagger}

X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate–binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.

1 INSERM UMR745, University Paris-Descartes, 75279 Paris, France.
2 Department of Pediatric Endocrinology and Neurology, Hôpital Saint-Vincent de Paul, Assistance Publique–Hôpitaux de Paris, 82 Avenue Denfert-Rochereau, 75674 Paris, France.
3 Department of Biotherapy, Hôpital Necker-Enfants Malades, 75743 Paris, France.
4 INSERM UMR768, University Paris-Descartes, 75743 Paris, France.
5 Clinical Investigation Center in Biotherapy, Groupe Hospitalier Universitaire Ouest, Assistance Publique–Hôpitaux de Paris (Inserm), 75743 Paris, France.
6 National Center for Tumor Diseases and German Cancer Research Center (Deutsches Krebsforschungszentrum), 69120 Heidelberg, Germany.
7 117 Southwest 72nd Place, Gainesville, FL 32608, USA.
8 Department of Pediatric Immuno-Hematology, Hôpital Necker-Enfants Malades, 75743 Paris, France.
9 Nature Publishing Group, New York, NY 10013–1917, USA.
10 13687 Quinton Road, San Diego, CA 92129, USA.
11 Department of Biochemistry, Hôpital Saint-Vincent de Paul, 75674 Paris, France.
12 Genosafe, 91002 Evry, France.
13 Commissariatà L’Energie Atomique (CEA), Institute of Emerging Diseases and Innovative Therapies (iMETI), Fontenay-aux-Roses 92265, France.
14 INSERM U962 and Université de Paris XI, CEA-iMETI, Fontenay-aux-Roses 92265, France.
15 Genetics Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: patrick.aubourg{at}inserm.fr

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