It is exciting!
In the preview by Luigi Naldini
Cartier et al. report another major advance—the successful first clinical testing of an HIV-derived vector in hematopoietic stem cell (HSC)–based gene therapy. The procedure was used to treat a severe neurodegenerative disease, X-linked adrenoleukodystrophy (ALD), and the results indicate stable expression of a therapeutic gene in a substantial fraction of patients' hematopoietic cells, as well as clinical benefits.
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Although many questions remain to be fully settled, this study clearly supports further testing of HSC-based gene therapy in ALD and other diseases and represents a long-sought rewarding achievement in the field of gene therapy.
Science. 2009 Nov 6;326(5954):818-23.
Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.
Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P.
INSERM UMR745, University Paris-Descartes, 75279 Paris, France.
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.
My notes
"The cells were then infected with a replication-defective HIV-1–derived lentiviral vector (CG1711 hALD) expressing wild-type ABCD1 cDNA under the control of the MND (myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer binding site substituted) promoter (10)."
"Because lentiviral correction does not provide human or mouse ALD HSCs with a selective growth advantage, we used a full myeloablation regimen, as this step would most likely increase the engraftment of transduced HSCs by removal of resident non-transduced HSCs."
"The procedure was clinically uneventful. Hematopoietic recovery occurred at days 13 to 15 after transplant and was sustained thereafter."
"In our study, we took advantage of new deep-sequencing technologies for genome-wide monitoring of lentivirusmarked HSC clonality in the patients. Although we did not detect obvious clonal skewing or dominance in hematopoiesis, a longer follow-up and a larger sample size will be required to verify that the potential for genotoxicity of lentiviral vectors in this application is low."
"In the current study, long-lasting expression of ALD protein in ~15% of monocytes (CD14+), a population of cells that have the same myelomonocytic
origin as bone marrow–derived brain microglia (27), was sufficient to obtain comparable neurological benefits after gene transfer into autologous HSCs, probably because ALD protein is overexpressed in microglial cells that derive from transduced CD34+ cells (28)."
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