Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates
G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, β-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain β-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Molecular therapy - 23(2015), 3, Seite 414 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Walia, Jagdeep S [VerfasserIn] |
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| Links: |
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| doi: |
10.1038/mt.2014.240 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates |
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| 520 | |a G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, β-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain β-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy. | ||
| 650 | 4 | |a Inflammation - mortality | |
| 650 | 4 | |a Lysosomes - enzymology | |
| 650 | 4 | |a Genetic Vectors - administration & dosage | |
| 650 | 4 | |a Genetic Therapy - methods | |
| 650 | 4 | |a Lung Neoplasms - etiology | |
| 650 | 4 | |a Sandhoff Disease - mortality | |
| 650 | 4 | |a G(M2) Ganglioside - metabolism | |
| 650 | 4 | |a Motor Activity - genetics | |
| 650 | 4 | |a Liver Neoplasms - etiology | |
| 650 | 4 | |a Lysosomes - pathology | |
| 650 | 4 | |a Brain - pathology | |
| 650 | 4 | |a Inflammation - pathology | |
| 650 | 4 | |a Lung Neoplasms - pathology | |
| 650 | 4 | |a Dependovirus - genetics | |
| 650 | 4 | |a beta-Hexosaminidase beta Chain - genetics | |
| 650 | 4 | |a Brain - enzymology | |
| 650 | 4 | |a Liver Neoplasms - pathology | |
| 650 | 4 | |a Sandhoff Disease - therapy | |
| 650 | 4 | |a Inflammation - therapy | |
| 650 | 4 | |a Inflammation - genetics | |
| 650 | 4 | |a Sandhoff Disease - pathology | |
| 650 | 4 | |a Sandhoff Disease - genetics | |
| 650 | 4 | |a Genetic Vectors - adverse effects | |
| 650 | 4 | |a beta-Hexosaminidase beta Chain - metabolism | |
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| 700 | 1 | |a Hurlbut, David |4 oth | |
| 700 | 1 | |a Hemming, Richard |4 oth | |
| 700 | 1 | |a Kobinger, Gary P |4 oth | |
| 700 | 1 | |a Triggs-Raine, Barbara |4 oth | |
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| 773 | 1 | 8 | |g volume:23 |g year:2015 |g number:3 |g pages:414 |
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