Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of β-glucuronidase-deficient mice
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作者:
Passini, MA
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Passini, MA
Watson, DJ
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Watson, DJ
Vite, CH
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Vite, CH
Landsburg, DJ
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Landsburg, DJ
Feigenbaum, AL
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Feigenbaum, AL
Wolfe, JH
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机构:Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
Wolfe, JH
机构:
[1] Childrens Hosp Philadelphia, Abramson Res Ctr 502G, Div Neurol, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Vet Med, Ctr Comparat Med Genet, Philadelphia, PA 19104 USA
Inherited metabolic disorders that affect the central nervous system typically result in pathology throughout the brain; thus, gene therapy strategies need to achieve widespread delivery. We previously found that although intraventricular injection of the neonatal mouse brain with adeno-associated virus serotype 2 (AAV2) results in dispersed gene delivery, many brain structures were poorly transduced. This limitation may be overcome by using different AAV serotypes because the capsid proteins use different cellular receptors for entry, which may allow enhanced global targeting of the brain. We tested this with AAV1 and AAV5 vectors. AAV5 showed very limited brain transduction after neonatal injection, even though it has different transduction patterns than AAV2 in adult brain injections. In contrast, AAV1 vectors, which have not been tested in the brain, showed robust widespread transduction. Complementary patterns of transduction between AAV1 and AAV2 were established and maintained in the adult brain after neonatal injection. In the majority of structures, AAV1 transduced many more cells than AAV2. Both vectors transduced mostly neurons, indicating that differential expression of receptors on the surfaces of neurons occurs in the developing brain. The number of cells positive for a vector-encoded secreted enzyme (beta-glucuronidase) was notably greater and more widespread in AAV1-injected brains. A comprehensive analysis of AAV1-treated brains from beta-glucuronidase-deficient mice (mucopolysaccharidosis type VII) showed complete reversal of pathology in all areas of the brain for at least 1 year, demonstrating that the combination of this serotype and experimental strategy is therapeutically effective for treating global neurometabolic disorders.
机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Alisky, JM
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Hughes, SM
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Hughes, SM
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Sauter, SL
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Sauter, SL
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Jolly, D
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Jolly, D
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Dubensky, TW
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Dubensky, TW
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Staber, PD
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Staber, PD
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Chiorini, JA
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Chiorini, JA
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Davidson, BL
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Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USAUniv Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Brooks, AI
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Stein, CS
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Stein, CS
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Hughes, SM
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Hughes, SM
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Heth, J
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Heth, J
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McCray, PM
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
McCray, PM
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Sauter, SL
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Sauter, SL
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Johnston, JC
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Johnston, JC
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Cory-Slechta, DA
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Cory-Slechta, DA
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Federoff, HJ
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Federoff, HJ
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Davidson, BL
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Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USAUniv Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Alisky, JM
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Hughes, SM
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Hughes, SM
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Sauter, SL
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Sauter, SL
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Jolly, D
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Jolly, D
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Dubensky, TW
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Dubensky, TW
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Staber, PD
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Staber, PD
;
Chiorini, JA
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机构:Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
Chiorini, JA
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Davidson, BL
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机构:
Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USAUniv Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Brooks, AI
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Stein, CS
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Stein, CS
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Hughes, SM
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Hughes, SM
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Heth, J
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Heth, J
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McCray, PM
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
McCray, PM
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Sauter, SL
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Sauter, SL
;
Johnston, JC
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Johnston, JC
;
Cory-Slechta, DA
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Cory-Slechta, DA
;
Federoff, HJ
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机构:Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA
Federoff, HJ
;
Davidson, BL
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机构:
Univ Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USAUniv Iowa, Coll Med, Program Gene Therapy, Dept Neurol, Iowa City, IA 52242 USA