Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

摘要: GM2 gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using Sandhoff disease (SD) mouse model (Hexb−/−) of the gangliosidoses, we tested potential systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct neurological phenotype. Neonatal or adult SD normal mice were intravenously injected with AAV9-HexB –LacZ monitored for serum activity, motor function, survival. Brain ganglioside, inflammation assessed at experimental week 43, an earlier humane end point. AAV9-LacZ died by 17 weeks age, whereas all neonatal AAV9-HexB–treated survived until 43 (P < 0.0001) only three exhibiting dysfunction. treated as adults between 35 weeks. SD-HexB–treated had significant increase brain reduction ganglioside storage neuroinflammation compared SD-HexB– SD-LacZ–treated groups. However, weeks, 8 10 neonatal-HexB control exhibited liver lung tumors. This study demonstrates long-term correction other through early rAAV9 based systemic gene therapy.