Intracisternal AAV9-MAG- <i>hABCD1</i> Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice

Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 (<i>ABCD1</i>) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG-<i>hABCD1</i> vector injected intravenously in the neonatal period prevented the disease in 2-year-old <i>Abcd1-/-</i> mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of <i>Abcd1-/-</i> mice start losing balance and motricity. As soon as 1-3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice (<i>n</i> = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice (<i>n</i> = 34). In five white matter regions of the cervical spinal cord, <i>hABCD1</i> expression at 24 months of age was present in 22% (18-27) of oligodendrocytes (OLs) and 22% (17-26) of astrocytes and not detected in neurons or microglia. Abundant <i>hABCD1</i> expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG-<i>hABCD1</i> vector at an early symptomatic stage of the <i>Abcd1-/-</i> mouse model paves a new oligotropic way for the gene therapy of AMN.