Gene therapy for leukodystrophy: progress, challenges and opportunities

Introduction: Leukodystrophies have long been considered untreatable. Recently, autologous transplantation of hematopoietic stem cells genetically corrected with lentiviral vectors showed clear benefit in X-linked adrenoleukodystrophy and metachromatic leukodystrophy, either at a very early stage of disease or in pre-symptomatic patients. These first successes still need, however, to be extended to a larger number of patients.Areas covered: The rationale, preclinical proof-of-concept research, and outcome of hematopoietic stem cell gene therapy trials with lentiviral vector in X-linked adrenoleukodystrophy and metachromatic leukodystrophy are provided. Potential application of this gene therapy strategy to Krabbe disease (globoid cell leukodystrophy) is discussed. Progresses in adeno-associated virus vectorology and vector delivery to target therapeutic gene in oligodendrocytes and astrocytes for many other leukodystrophies are explained.Expert Opinion: Each leukodystrophy will require a specific gene therapy strategy, from vector design to viral vector delivery and window of therapeutic intervention. Yet, the very encouraging results obtained in two leukodystrophies, as well as the successes of gene therapy in various severe inherited diseases of the blood, eye and immune systems open a real hope that, in a relatively near future, several leukodystrophies will become treatable by gene therapy.