초록
<P><B>Abstract</B><P>Background<P>Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α‐galactosidase A (α‐Gal A) encoded by the <I>GLA</I> 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.</P></P><P>Methods<P>α‐Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 10<SUP>11</SUP> viral genomes [vg]) or AAV9 (1 × 10<SUP>11</SUP> or 2 × 10<SUP>12</SUP> vg) vectors carrying human <I>GLA</I> (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.</P></P><P>Results<P>The plasma α‐Gal A enzymatic activity was three‐fold higher in the AAV9 2 × 10<SUP>12</SUP> vg group than wild‐type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 10<SUP>12</SUP> 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<SUP>12</SUP> 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<SUP>12</SUP> vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced.</P></P><P>Conclusions<P>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.</P></P></P>