title: Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease.
abstract: Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.
authors.affiliation: Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA. jim.dodge@genzyme.com
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.forename: Antonius
authors.initials: A
authors.lastname: Song
authors.forename: Jie
authors.initials: J
authors.lastname: Bu
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Taksir
authors.forename: Denise
authors.initials: D
authors.lastname: Griffiths
authors.forename: Michael A
authors.initials: MA
authors.lastname: Zhao
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Catherine R
authors.initials: CR
authors.lastname: O'Riordan
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D064026:Calbindins; D002452:Cell Count; D002490:Central Nervous System / Q000201:enzymology / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009542:Niemann-Pick Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D011689:Purkinje Cells / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D064026:Calbindins; D064030:S100 Calcium Binding Protein G; D013109:Sphingomyelins; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase