Gene therapy researchers have treated two boys with X-linked adrenoleukodystrophy (X-ALD), a demyelinating disease highlighted in the movie “Lorenzo's Oil.” Such individuals are normally treated with allogeneic hematopoietic stem cell (HSC) transplantation, which results in donor-derived microglia in the brain. Patrick Aubourg and his colleagues1 chose two subjects who did not have a matched donor. They corrected the aberrant gene in the subjects' HSCs with a lentiviral vector derived from HIV; such vectors can transduce HSCs with particular efficiency. Fourteen to sixteen months after infusion of the genetically corrected cells, progressive demyelination in the brain stopped, an outcome comparable to that achieved by conventional transplantation treatment.

Four HSCs (nuclei in blue) isolated from a boy with X-linked ALD 2 years after gene therapy. One of the cells shows expression of ALD, encoded by the integrated lentiviral vector; ALD is expressed in peroxisomes (red dots). Eighteen percent of HSCs in this individual expressed ALD 2 years after treatment. Credit: Patrick Aubourg

Donald B. Kohn:

This is the first trial of gene therapy with HSCs where a full marrow cytoablative conditioning regimen, the standard preparative regimen for allogeneic HSC transplant, was used before autologous transplant of gene-corrected HSCs. The combination of rigorous marrow ablation and efficient gene transfer to HSCs by a lentiviral vector resulted in relatively high numbers of blood cells (and presumably central nervous system microglial cells) derived from HSCs containing and expressing the disease-correcting gene. This approach allowed the subjects to realize clinical benefits akin to those seen in the standard treatment for X-ALD, allogeneic HSC transplant, while avoiding the major side effects such as graft-versus-host disease. The approach prevented further demyelination of the central nervous system and stabilized neurological function. These findings herald the imminent success of this approach for applications to other blood cell disorders, such as sickle cell anemia and thalassemia, lysosomal storage diseases and immune deficiencies both inherited and acquired (such as AIDS).

Professor at the University of Southern California, Los Angeles, California, USA.

Beverly Davidson:

The work by Cartier et al.1 shows the utility of gene-corrected HSCs to treat a fatal, recessively inherited neurodegenerative disease, X-linked ALD. Lentiviruses with their enhancer elements inactivated were used for gene correction because of their improved safety profile over murine gammaretroviral vectors, and because they can infect both dividing and nondividing cells. This platform provides a method for transducing a higher percentage of HSCs, which, after engraftment, should translate into improved levels of correction. With respect to X-linked ALD, demyelination and focal blood-brain barrier compromise would facilitate trafficking and deposition of cells derived from the transduced HSCs. Overall, the work reflects favorably on this approach for other neurogenetic disorders, such as metachromatic leukodystrophy, that, as part of their phenotype, provide a milieu for attracting genetically corrected cells from the periphery into the brain.

Professor of Medicine, University of Iowa, Iowa City, Iowa, USA.

David Williams:

The approach resulted in stable introduction of the corrective gene, apparently reduced brain inflammation and slowed the course of disease. Extensive analysis of vector insertion sites in the genome showed no evidence of untoward 'clonal skewing' in hematopoietic cells. Thus, overall, the approach is a clear advance for the field. It provides high gene transfer levels, without selective pressure, to provide phenotypic correction; increased speed of therapeutic intervention, as donor identification is not required; reduced side effects related to graft-versus-host disease; and an apparent high safety profile related to insertional mutagenesis. Clearly, more test subjects and more follow-up are required to fully evaluate the impact of this approach more broadly, but it might be applicable to many other monogenic blood diseases.

Chief, Division of Hematology/Oncology, Children's Hospital Boston, and Fikes Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.