Long-term inhibition of glycosphingolipid accumulation in Fabry model mice by a single systemic injection of AAV1 vector in the neonatal period.

Fabry disease is caused by the deficiency of lysosomal alpha-galactosidase A (alpha-gal A) and usually develops clinical manifestations during childhood/adolescence. Adult Fabry model mice have been successfully treated by various viral vectors. Here, in order to examine the feasibility of preventive gene therapy, we compared AAV vector-mediated gene transfer into neonatal and adult model mice. AAV serotype 1 vector (AAV1) carrying human alpha-gal A cDNA driven by the CAG promoter was intravenously injected into adult (12 weeks old) and neonatal (2 days old) Fabry model mice, and were sacrificed for detailed examination 25 weeks after vector injection. AAV1 vector preferentially transduced the liver in male adult and sustained high concentration of alpha-gal A was detected in the liver, heart and plasma. In contrast, AAV1-mediated gene expression was suppressed in similarly treated female adult mice. When the vector was systemically injected into neonates, moderate increase in plasma alpha-gal A and cardiac-specific expression of alpha-gal A were observed independently of mouse sex. The high levels of alpha-gal A activity in the heart appear to be due to the strong activity of the CAG promoter in the heart. Globotriaosylceramide (Gb3) accumulation was efficiently inhibited in the liver and heart by a single injection into both adult and neonatal animals. The biodistribution of the AAV1 vector and levels of alpha-gal A expression are markedly different between adult and neonatal mice. Neonatal injection is effective to inhibit Gb3 accumulation and therefore, might help prevent failure of major organs during adulthood.