Gene therapy strategies for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is the most frequently seen genetic disorder involving the myelin of the central nervous system. The cerebral form affects mainly boys between five to 12 years, leading to vegetative state or death within two to four years. The adult form affects the spinal cord, leading to severe paraplegia often complicated by cerebral demyelination. The ALD gene encodes an ATP-binding cassette transporter involved in the transport of very long chain fatty acids into peroxysomes. Specific subpopulations of oligodendrocytes and microglia are particularly affected by the ALD gene mutation and thus should be the target cells of gene therapy approaches. Two different and potentially complementary therapeutic strategies are currently evaluated. The first approach aims at replacing the endogenous brain microglia from patients by autotransplantation of genetically corrected hematopoietic stem cells using a lentiviral vector. The second approach aims at targeting directly the ALD gene into brain glial cells using stereotactic injections of viral vectors.