Haematopoietic stem cell gene therapy for ALD

13 November 2009

French researchers have reported the results of a new form of gene therapy used to treat patients with the genetic neurodegenerative disease X-linked adrenoleukodystrophy (ALD). Caused by mutations in the ABCD1 gene that prevent the formation of normal ALD protein, patients develop progressive loss of the myelin sheath that protects nerve cells. Death typically occurs before adolescence; the only treatment is a full bone marrow transplant, which requires a matched donor and is in itself a dangerous procedure, and which must also take place early in life before the demyelination progresses too far, since it is irreversible.                      

Now researchers have treated haematopoietic stem cells (blood cell precursors) from two seven-year old ALD patients with an HIV-1 derived lentivirus vector carrying the normal ABCD1 gene [Cartier N et al. (2009) Science. 326(5954):818-23]. The patients had aggressive chemotherapy to suppress normal bone marrow production of haematopoietic stem cells followed by administration of the treated stem cells. Since these stem cells were derived from the patients’ own cells, there was no risk of immune rejection as there would be with imperfectly matched donor cells.

Blood cell analysis suggested that around 15% of the reconstituted blood cells in the patients contained normal, healthy copies of the ABCD1 gene. Brain scans and tests of cognitive function showed a halt in disease progression after 14–16 months that has persisted for a further 12 months. There have been no signs of cancer; the major risk from gene therapy (especially using virus-derived vectors) is of insertional mutagenesis where the vector inserts into a place in the recipient cell’s genome that drives the formation of a tumour (see previous news). Analysis of the sites of vector insertion to date reportedly did not show any signs that the vectors were inserting in any one particular site ie. that there was any preferential replication of cells carrying the insert in a particular position, which might be a precursor of cancer formation.

Comment: This was a very small trial; while promising, it is still early days, and it is possible that over time the therapeutic effect of the gene therapy could deteriorate, or leukaemia develop in either of the two patients. However, without this treatment, the outlook for these two boys (for whom no matched bone marrow donor was available) was extremely bleak; for the moment, at least, they have been cured. Further trials with patients in similar positions are certainly warranted  - and no doubt eagerly sought by the patients’ families.

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