Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris

Last week's Science magazine reported what seems likely to count as one of gene transfer's greatest clinical successes to date: stabilization of adrenoleukodystrophy in two boys receiving genetically modified blood stem cells. Preliminary results of this study had been presented at this summer's American Society of Gene and Cell Therapy meeting.

Adrenoleukodystrophy (ALD) is a rare hereditary brain disorder in which a deficiency in a gene, ABCD1, causes degeneration of tissues (myelin) that insulate cells in the central nervous system. The disease is familiar to many because of its most famous patient, Lorenzo Odone, whose story was featured in the movie Lorenzo's Oil. Untreated, ALD is invariably fatal.

Because myelin cells originate from blood stem cells, researchers had previously used bone marrow transplantation to successfully halt progression of demyelination in ALD patients. However, bone marrow transplantation has two severe limitations: many patients lack matched bone marrow donors; second, even when a matched donor is available, the procedure is burdensome and risky.

In this most recent study, researchers at Hôpital Necker in Paris transplanted genetically modified bone marrow cells into two Spanish boys who lacked matched bone marrow donors. The boys were also given myeloablative conditioning- a type of chemotherapy that increases the likelihood that genetically modified cells will repopulate the bone marrow. The Science report showed:

1- genetically modified cells did, indeed, survive and were maintained at stable levels for two years.

2- the modified cells expressed the therapeutic gene, ABCD1, again for two years.

3- brain demyelination was halted after 14 months- the timing is similar to what would occur for patients receiving bone marrow transplantation.

4- the two boys did not appear to decline on various measures of neurological or verbal tests, as would almost certainly have occurred with the natural course of ALD.

5- the authors did not detect "clonal dominance" in their modified cells– that is, evidence that genetically modified cells were poised to cause a malignancy.

In an accompanying editorial, Luigi Naldini calls this study a "Comeback for Gene Therapy," describing it as a "long-sought rewarding achievement in the field of gene therapy." In my next post, I will discuss some implications, interpretations, and other interesting dimensions of this very encouraging study (photo credit: tgif28, chalk graffiti at Hopital Necker, 2009)