title: Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jagdeep S
authors.initials: JS
authors.lastname: Walia
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Naderah
authors.initials: N
authors.lastname: Altaleb
authors.affiliation: 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bello
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Christa
authors.initials: C
authors.lastname: Kruck
authors.affiliation: Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: LaFave
authors.affiliation: Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Varshney
authors.affiliation: Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Burgess
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Chowdhury
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hurlbut
authors.affiliation: Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Hemming
authors.affiliation: 1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada [2] Special Pathogens Program, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005678:G(M2) Ganglioside / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects; D007249:Inflammation / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D007275:Injections, Intravenous; D007763:Lac Operon; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D012497:Sandhoff Disease / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D054821:beta-Hexosaminidase beta Chain / Q000235:genetics* / Q000378:metabolism
chemical_list: D005678:G(M2) Ganglioside; D054821:beta-Hexosaminidase beta Chain