Therapeutic strategy for Fabry disease by intravenous administration of adeno‐associated virus 2 or 9 in α‐galactosidase A‐deficient mice

Abstract Background Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α‐galactosidase A (α‐Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α‐Gal A, in the organs. Adeno‐associated virus (AAV)‐mediated gene therapy is a promising treatment for FD. Methods α‐Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 10 11 viral genomes [vg]) or AAV9 (1 × 10 11 or 2 × 10 12 vg) vectors carrying human GLA (AAV‐hGLA), and plasma, brain, heart, liver and kidney were tested for α‐Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. Results The plasma α‐Gal A enzymatic activity was three‐fold higher in the AAV9 2 × 10 12 vg group than wild‐type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 10 12 vg group, the level of α‐Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 10 12 vg group significantly increased compared to the phosphate‐buffered‐saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 10 12 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. Conclusions Systemic injection of AAV9‐hGLA resulted in α‐Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α‐Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.