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

Autor: Walia JS; 1] Department of Pediatrics, Queen's University, Kingston, Ontario, Canada [2] Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada [3] Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada [4] Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada., Altaleb N; Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada., Bello A; 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Kruck C; Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada., LaFave MC; Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Varshney GK; Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Burgess SM; Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Chowdhury B; Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada., Hurlbut D; Department of Pathology & Molecular Medicine, Queen's University, Kingston, Ontario, Canada., Hemming R; Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada., Kobinger GP; 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Triggs-Raine B; 1] Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada [2] Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada [3] Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
Jazyk: angličtina
Zdroj: Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2015 Mar; Vol. 23 (3), pp. 414-22. Date of Electronic Publication: 2014 Dec 17.
DOI: 10.1038/mt.2014.240
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: