PMID- 25515709 OWN - NLM STAT- MEDLINE DCOM- 20151116 LR - 20220318 IS - 1525-0024 (Electronic) IS - 1525-0016 (Print) IS - 1525-0016 (Linking) VI - 23 IP - 3 DP - 2015 Mar TI - Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates. PG - 414-22 LID - 10.1038/mt.2014.240 [doi] AB - G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in beta-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 beta-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, beta-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 beta-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. FAU - Walia, Jagdeep S AU - Walia JS AD - 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. FAU - Altaleb, Naderah AU - Altaleb N AD - Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. FAU - Bello, Alexander AU - Bello A AD - 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada. FAU - Kruck, Christa AU - Kruck C AD - Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. FAU - LaFave, Matthew C AU - LaFave MC AD - Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Varshney, Gaurav K AU - Varshney GK AD - Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Burgess, Shawn M AU - Burgess SM AD - Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Chowdhury, Biswajit AU - Chowdhury B AD - Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. FAU - Hurlbut, David AU - Hurlbut D AD - Department of Pathology & Molecular Medicine, Queen's University, Kingston, Ontario, Canada. FAU - Hemming, Richard AU - Hemming R AD - Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. FAU - Kobinger, Gary P AU - Kobinger GP AD - 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada. FAU - Triggs-Raine, Barbara AU - Triggs-Raine B AD - 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. LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20141217 PL - United States TA - Mol Ther JT - Molecular therapy : the journal of the American Society of Gene Therapy JID - 100890581 RN - 19600-01-2 (G(M2) Ganglioside) RN - EC 3.2.1.52 (beta-Hexosaminidase beta Chain) SB - IM MH - Age Factors MH - Animals MH - Animals, Newborn MH - Brain/enzymology/pathology MH - Dependovirus/*genetics MH - Disease Models, Animal MH - Female MH - G(M2) Ganglioside/*metabolism MH - Gene Expression MH - Genetic Therapy/*methods MH - Genetic Vectors/*administration & dosage/adverse effects MH - Inflammation/genetics/mortality/pathology/therapy MH - Injections, Intravenous MH - Lac Operon MH - Liver Neoplasms/etiology/pathology MH - Lung Neoplasms/etiology/pathology MH - Lysosomes/enzymology/pathology MH - Male MH - Mice MH - Mice, Knockout MH - Motor Activity/genetics MH - Sandhoff Disease/genetics/mortality/pathology/*therapy MH - Survival Analysis MH - beta-Hexosaminidase beta Chain/*genetics/metabolism PMC - PMC4351464 EDAT- 2014/12/18 06:00 MHDA- 2015/11/17 06:00 PMCR- 2016/03/01 CRDT- 2014/12/18 06:00 PHST- 2014/09/15 00:00 [received] PHST- 2014/12/02 00:00 [accepted] PHST- 2014/12/18 06:00 [entrez] PHST- 2014/12/18 06:00 [pubmed] PHST- 2015/11/17 06:00 [medline] PHST- 2016/03/01 00:00 [pmc-release] AID - S1525-0016(16)30055-7 [pii] AID - 10.1038/mt.2014.240 [doi] PST - ppublish SO - Mol Ther. 2015 Mar;23(3):414-22. doi: 10.1038/mt.2014.240. Epub 2014 Dec 17.