• DOI:10.1126/science.1171242
• Corpus ID: 27783

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

@article{Cartier2009HematopoieticSC,
  title={Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy},
  author={Nathalie Cartier and Salima Hacein-Bey-Abina and Cynthia C. Bartholomae and Gabor Istvan Veres and Manfred Schmidt and Ina Kutschera and Michel Vidaud and Ulrich Abel and Liliane Dal-Cortivo and Laure Caccavelli and Nizar Mahlaoui and V{\'e}ronique Kiermer and Denice M. Mittelstaedt and C{\'e}line Bellesme and Najiba Lahlou and François Lefrère and St{\'e}phane Blanche and Muriel Audit and Emmanuel Payen and Philippe Leboulch and Bruno L’homme and Pierre Bougn{\`e}res and Christof von Kalle and Alain Fischer and Marina Cavazzana‐Calvo and Patrick R. Aubourg},
  journal={Science},
  year={2009},
  volume={326},
  pages={818 - 823}
}

• N. Cartier, S. Hacein-Bey-Abina, +23 authors P. Aubourg
• Published 6 November 2009
• Medicine, Biology
• Science

Slowing Brain Disease with Gene Therapy X-linked adrenoleukodystrophy (ALD), the hereditary brain demyelinating disorder that was featured in the movie “Lorenzo's Oil,” is typically treated by transplantation of bone marrow from matched donors. This treatment slows progression of the disease by introducing cells that differentiate into myelin-producing cells. Cartier et al. (p. 818; see Perspective by Naldini) tested an alternative gene therapy–based approach in two young patients without matched donors. A lentiviral vector was used to introduce a wild-type copy of the ALD gene into the patients' hematopoietic stem cells ex vivo. The modified cells were then infused back into the patients. Expression of the transferred gene was still detectable in the patients' blood cells 2 years later, and both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants. Lentiviral-mediated gene therapy of hematopoietic stem cells delays disease progression in patients with a fatal brain disorder. 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.