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Systemic administration of AAV8-?-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.

ABSTRACT: In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding ?-galactosidase A (?-gal). As in mice, sustained expression in monkeys attenuated antibody responses to ?-gal. However, this effect was not robust, and sustained ?-gal levels were 1-2 logs lower than those achieved in male mice at the same vector dose. Because our mouse studies had shown that antibody levels were directly related to expression levels, several strategies were evaluated to increase expression in monkeys. Unlike mice, expression in monkeys did not respond to androgens. Local delivery to the liver, immune suppression, a self-complementary vector and pharmacologic approaches similarly failed to increase expression. While equivalent vector copies reached mouse and primate liver and there were no apparent differences in vector form, methylation or deamination, transgene expression was limited at the mRNA level in monkeys. These results suggest that compared to mice, transcription from an AAV8 vector in monkeys can be significantly reduced. They also suggest some current limits on achieving clinically useful antibody reduction and therapeutic benefit for lysosomal storage diseases using a systemic AAV8-based approach.

SUBMITTER: Nietupski JB

PROVIDER: S-EPMC3222520 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Systemic administration of AAV8-α-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.

Nietupski Jennifer B JB Hurlbut Gregory D GD Ziegler Robin J RJ Chu Qiuming Q Hodges Bradley L BL Ashe Karen M KM Bree Mark M Cheng Seng H SH Gregory Richard J RJ Marshall John J Scheule Ronald K RK

Molecular therapy : the journal of the American Society of Gene Therapy 20110628 11

In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding α-galactosidase A (α-gal). As in mice, sustained expression in monkeys attenuated antibody responses to α-gal. However, this effect was not robust, and sustained α-gal levels were 1-2 logs lower than thos ...[more]

PMID: 21712814

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Project description:Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts broad effects on consciousness and perception. Since NMDA receptor antagonists induce cognitive impairments, ketamine has been used for translational research on several psychiatric diseases, such as schizophrenia. Whereas the effects of ketamine on cognitive functions have been extensively studied, studies on the effects of ketamine on simple sensory information processing remain limited. In this study, we investigated the cortex-wide effects of ketamine administration on auditory information processing in nonhuman primates using whole-cortical electrocorticography (ECoG). We first recorded ECoG from awake monkeys on presenting auditory stimuli of different frequencies or different durations. We observed auditory evoked responses (AERs) across the cortex, including in frontal, parietal, and temporal areas, while feature-specific responses were obtained around the temporal sulcus. Next, we examined the effects of ketamine on cortical auditory information processing. We conducted ECoG recordings from monkeys that had been administered anesthetic doses of ketamine from 10 to 180 min following administration. We observed significant changes in stimulus feature-specific responses. Electrodes showing a frequency preference or offset responses were altered following ketamine administration, while those of the AERs were not strongly influenced. However, the frequency preference of a selected electrode was not significantly altered by ketamine administration over time following administration, while the imbalances in the onset and offset persisted over the course of 150 min following ketamine administration in all three monkeys. These results suggest that ketamine affects the ability to distinguish between sound frequency and duration in different ways. In conclusion, future research on the NMDA sensitivity of cortical wide sensory information processing may provide a new perspective into the development of nonhuman primate models of psychiatric disorders.

Dataset Information

Systemic administration of AAV8-?-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.

Publications

Systemic administration of AAV8-α-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.

Similar Datasets

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