Research ArticleGloboid Cell Leukodystrophy

Identification of Hematopoietic Stem Cell–Specific miRNAs Enables Gene Therapy of Globoid Cell Leukodystrophy

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Science Translational Medicine  17 Nov 2010:
Vol. 2, Issue 58, pp. 58ra84
DOI: 10.1126/scitranslmed.3001522

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Scratching the Surface of the Holy Grail

In Monty Python and the Holy Grail, when King Arthur cuts off one of the arms of the Black Knight, he claims it is only a scratch. Similarly, gene therapy—the insertion of genes into cells to reverse a condition or repair a biological process—has been heralded as a Holy Grail for the treatment of genetic diseases for nearly 40 years. Yet, the complications of gene therapy, including immune responses to the viral vector and cancers that result from insertional mutagenesis, are more comparable to a severed arm than a surface wound. However, researchers with the resiliency of the Black Knight have presided over recent successes, most notably in metastatic melanoma and immune cells, and have reignited the quest for gene therapy solutions to otherwise untreatable diseases. Gentner et al. build on these successes by identifying new microRNAs that can restrict gene therapy vectors to particular immune cell types and thus be used to safely treat globoid cell leukodystrophy (also known as Krabbe disease).

Globoid cell leukodystrophy is a rare metabolic disorder caused by a mutation in a lysosomal enzyme called galactocerebrosidase (GALC). In patients who carry the mutation in both copies of the GALC gene, unmetabolized lipids accumulate in myelin-secreting glial cells, rendering them unable to produce the myelin sheath that normally wraps and protects nerves. This aberration results in severe and often fatal degeneration of motor skills. Bone marrow transplantation has been shown to benefit these patients if the disease is caught early enough. Genetic manipulation of the hematopoietic stem and progenitor cells (HSPCs) found in bone marrow may improve this therapy; however, high-level GALC expression in HSPCs, but not in more differentiated immune cells, is toxic.

To address this issue, Gentner et al. identified miRNAs—short RNA sequences that often silence gene expression—that were specifically expressed in HSPCs but not in more differentiated cells. They then used these miRNAs in a GALC/HSPC gene therapy system to suppress GALC function in HSPCs upon transfer into a mouse model of globoid cell leukodystrophy. As these cells matured, amounts of HSPC-specific miRNA decreased and GALC expression increased. This approach protected the HSPCs from GALC toxicity, but allowed for successful gene therapy of the disease. In addition, these hematopoietic stem cell–specific miRNAs could be used as simple markers with which to isolate HSPCs for study and transplantation. This work thus provides a basis for improvements in HSPC-mediated gene therapy and may offer globoid cell leukodystrophy patients a new therapeutic option that resembles a scratch more than a chop.


  • * These authors contributed equally to this work.

  • These authors share senior authorship.

  • Citation: B. Gentner, I. Visigalli, H. Hiramatsu, E. Lechman, S. Ungari, A. Giustacchini, G. Schira, M. Amendola, A. Quattrini, S. Martino, A. Orlacchio, J. E. Dick, A. Biffi, L. Naldini, Identification of Hematopoietic Stem Cell–Specific miRNAs Enables Gene Therapy of Globoid Cell Leukodystrophy. Sci. Transl. Med. 2, 58ra84 (2010).

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