title: Magnetic resonance imaging-guided delivery of adeno-associated virus type 2 to the primate brain for the treatment of lysosomal storage disorders.
abstract: Gene replacement therapy for the neurological deficits caused by lysosomal storage disorders, such as in Niemann-Pick disease type A, will require widespread expression of efficacious levels of acid sphingomyelinase (ASM) in the infant human brain. At present there is no treatment available for this devastating pediatric condition. This is partly because of inherent constraints associated with the efficient delivery of therapeutic agents into the CNS of higher order models. In this study we used an adeno-associated virus type 2 (AAV2) vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA) to transduce highly interconnected CNS regions such as the brainstem and thalamus. On the basis of our data showing global cortical expression of a secreted reporter after thalamic delivery in nonhuman primates (NHPs), we set out to investigate whether such widespread expression could be enhanced after brainstem infusion. To maximize delivery of the therapeutic transgene throughout the CNS, we combined a single brainstem infusion with bilateral thalamic infusions in naive NHPs. We found that enzymatic augmentation in brainstem, thalamic, cortical, as well subcortical areas provided convincing evidence that much of the large NHP brain can be transduced with as few as three injection sites.
authors.affiliation: Department of Neurosurgery, University of California San Francisco, 94103, USA.
authors.forename: E Aguilar
authors.initials: EA
authors.lastname: Salegio
authors.forename: A P
authors.initials: AP
authors.lastname: Kells
authors.forename: R M
authors.initials: RM
authors.lastname: Richardson
authors.forename: P
authors.initials: P
authors.lastname: Hadaczek
authors.forename: J
authors.initials: J
authors.lastname: Forsayeth
authors.forename: J
authors.initials: J
authors.lastname: Bringas
authors.forename: S P
authors.initials: SP
authors.lastname: Sardi
authors.forename: M A
authors.initials: MA
authors.lastname: Passini
authors.forename: L S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: S H
authors.initials: SH
authors.lastname: Cheng
authors.forename: M S
authors.initials: MS
authors.lastname: Fiandaca
authors.forename: K S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007430:Intraoperative Care; D016464:Lysosomal Storage Diseases / Q000235:genetics* / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D009474:Neurons / Q000378:metabolism; D011323:Primates; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000627:therapeutic use; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D013108:Sphingomyelin Phosphodiesterase
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