Intracisternal AAV9-MAG- Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice.

Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 () 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- vector injected intravenously in the neonatal period prevented the disease in 2-year-old mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of 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 ( = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice ( = 34). In five white matter regions of the cervical spinal cord, 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 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- vector at an early symptomatic stage of the mouse model paves a new oligotropic way for the gene therapy of AMN.