Adeno-associated virus vector-mediated transduction in the cat brain

Vite, Charles H.; Passini, Marco A.; Haskins, Mark E.; Wolfe, John H.

doi:10.1038/sj.gt.3302087

Cited by 103 publications

(69 citation statements)

References 43 publications

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“…For example, it has been reported that the transduction efficiency of serotype 1 and 5 is superior to AAV2 in the murine brain (29). Studies completed in both rats (6) and cats (30) demonstrated that the transduction efficiency for serotype 1 exceeds both serotypes 2 and 5. Our results support and extend these previous findings.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Dodge

Clarke

Song

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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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.axonal transport ͉ deep cerebellar nuclei ͉ gene therapy ͉ lysosomal storage diseases ͉ adeno-associated virus N iemann-Pick type A disease (NPA) is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Loss of ASM activity results in lysosomal sphingomyelin (SPM) accumulation, secondary metabolic defects such as aberrant cholesterol metabolism, and subsequently the loss of cellular function in various organ systems including the central nervous system (CNS) (1, 2). Previously, we demonstrated that intracerebral delivery of adeno-associated virus serotype-2 encoding human ASM (AAV2-hASM) is effective in correcting lysosomal storage pathology in ASM knockout (ASMKO) mice (3). Interestingly, correction of lysosomal storage pathology not only occurred at the injection site (i.e., hippocampus), but also in regions (e.g., entorhinal cortex) that send and͞or receive input from the injection site. This finding, in accordance with previous work (4), demonstrated that neuronal circuits can be used to achieve AAV vector and protein distribution via axonal transport to regions that are proximal or distal to the injection site.Despite our initial success with AAV2, investigation of the relative therapeutic efficacy of additional serotypes is warranted. Serotype-dependent variations in cellular tropism, rates of diffusion, and transduction efficiencies may translate into disparate levels of therapeutic efficacy (5, 6). Furthermore, we wish to show that AAV-mediated hASM expression prevents disease initiated neurodegeneration (i.e., Purkinje cell loss) and disturbances in motor function in ASMKO mice (7, §).To examine...

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Section: Discussionmentioning

confidence: 99%

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Dodge

Clarke

Song

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…An indication of effi cacy from focal intraparenchymal injections has also been observed in large animal models (e.g., cats and dogs) of various LSDs ( 119,(124)(125)(126)(127). However, despite these encouraging results, scaling this strategy to an infant brain is estimated to nevertheless require between 50 and 350 injection tracts, which is arguably impractical ( 124,127 ).…”

Section: Effi Cacy Of Intracranial Delivery Of Aav Vectors For Neuropmentioning

confidence: 98%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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“…In order for such an approach to be clinically effective, it seemed likely that widespread expression in target regions of the brain, cortex, and striatum would be needed. It has been reported that the transduction efficiency in the CNS of AAV1 is superior to that of AAV2 in various animal models, including mouse, rat, and cat (Vite et al, 2003;Wang et al, 2003;Burger et al, 2004). Significantly, however, there is to our knowledge no published report of AAV1 in the primate brain.…”

Section: Introductionmentioning

confidence: 68%

“…A number of reports have shown that the AAV1 serotype transduces the brain more efficiently than does AAV2 (Vite et al, 2003;Wang et al, 2003;Dodge et al, 2005). We have explored in nonhuman primates the utility of this serotype with a vector that encodes a humanized Renilla green fluorescent protein (hrGFP) for which the codon usage has been optimized for use in mammals (see patent WO=2004=005322).…”

Section: Discussionmentioning

confidence: 99%

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

Hadaczek¹,

Forsayeth²,

Mirek³

et al. 2008

Human Gene Therapy

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We used convection-enhanced delivery (CED) to characterize gene delivery mediated by adeno-associated virus type 1 (AAV1) by tracking expression of hrGFP (humanized green fluorescent protein from Renilla reniformis) into the striatum, basal forebrain, and corona radiata of monkey brain. Four cynomolgus monkeys received single infusions into corona radiata, putamen, and caudate. The other group (n ¼ 4) received infusions into basal forebrain. Thirty days after infusion animals were killed and their brains were processed for immunohistochemical evaluation. Volumetric analysis of GFP-positive brain areas was performed. AAV1-hrGFP infusions resulted in approximately 550, 700, and 73 mm 3 coverage after infusion into corona radiata, striatum, and basal forebrain, respectively. Aside from targeted regions, other brain structures also showed GFP signal (internal and external globus pallidus, subthalamic nucleus), supporting the idea that AAV1 is actively trafficked to regions distal from the infusion site. In addition to neuronal transduction, a significant nonneuronal cell population was transduced by AAV1 vector; for example, oligodendrocytes in corona radiata and astrocytes in the striatum. We observed a strong humoral and cell-mediated response against AAV1-hrGFP in transduced monkeys irrespective of the anatomic location of the infusion, as evidenced by induction of circulating anti-AAV1 and anti-hrGFP antibodies, as well as infiltration of CD4 + lymphocytes and upregulation of MHC-II in regions infused with vector. We conclude that transduction of antigen-presenting cells within the CNS is a likely cause of this response and that caution is warranted when foreign transgenes are used as reporters in gene therapy studies with vectors with broader tropism than AAV2.

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Adeno-associated virus vector-mediated transduction in the cat brain

Cited by 103 publications

References 43 publications

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Gene therapy for the neurological manifestations in lysosomal storage disorders

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

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