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Preferential transduction of parvalbumin-expressing cortical neurons by AAV-mDLX5/6 vectors.

ABSTRACT: A major goal of modern neuroscience is to understand the functions of the varied neuronal types that comprise the mammalian brain. Toward this end, some types of neurons can be targeted and manipulated with enhancer-bearing AAV vectors. These vectors hold great promise to advance basic and translational neuroscience, but to realize this potential, their selectivity must be characterized. In this study, we investigated the selectivity of AAV vectors carrying an enhancer of the murine Dlx5 and Dlx6 genes. Vectors were injected into the visual cortex of two macaque monkeys, the frontal cortex of two others, and the somatosensory/motor cortex of three rats. Post-mortem immunostaining revealed that parvalbumin-expressing neurons were transduced efficiently in all cases but calretinin-expressing neurons were not. We speculate that this specificity is a consequence of differential activity of this DLX5/6 enhancer in adult neurons of different developmental lineages.

SUBMITTER: Yazdan-Shahmorad P

PROVIDER: S-EPMC10894992 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Preferential transduction of parvalbumin-expressing cortical neurons by AAV-mDLX5/6 vectors.

Yazdan-Shahmorad Padideh P Gibson Shane S Lee Joanne C JC Horwitz Gregory D GD

Frontiers in neuroscience 20240212

A major goal of modern neuroscience is to understand the functions of the varied neuronal types that comprise the mammalian brain. Toward this end, some types of neurons can be targeted and manipulated with enhancer-bearing AAV vectors. These vectors hold great promise to advance basic and translational neuroscience, but to realize this potential, their selectivity must be characterized. In this study, we investigated the selectivity of AAV vectors carrying an enhancer of the murine Dlx5 and Dlx ...[more]

PMID: 38410819

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Project description:Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is administered intravenously at high doses that cause liver-associated adverse events in 20%–30% of patients. Intrathecal routes of vector administration, such as the intra-cisterna magna route, provide efficient gene transduction to central nervous system cells while reducing off-target liver transduction. However, significant levels of liver transduction often occur upon intra-cisterna magna vector delivery in preclinical studies. Using vectors expressing monoclonal antibody transgenes, we examined whether passive transfer of adeno-associated virus-neutralizing antibodies as intravenous immunoglobulin before intrathecal adeno-associated virus delivery improved the safety of viral gene therapy targeting the central nervous system in mice and nonhuman primates. We used intracerebroventricular and intra-cisterna magna routes for vector administration to mice and nonhuman primates, respectively, and evaluated transgene expression and vector genome distribution. Our data indicate that pretreatment with intravenous immunoglobulin significantly reduced gene transduction to the liver and other peripheral organs but not to the central nervous system in both species. With further refinement, this method may improve the safety of adeno-associated virus-based, central nervous system-targeting gene therapies in clinical settings. Graphical abstract Off-target transduction during AAV gene therapy is associated with adverse side effects. Horiuchi et al. examined whether pretreatment with AAV-neutralizing antibodies prevented off-target transduction in mice and nonhuman primates receiving CNS-targeted gene therapy. Intravenous immunoglobulin pretreatment significantly reduced transduction of the liver and other peripheral organs but not the CNS.

Dataset Information

Preferential transduction of parvalbumin-expressing cortical neurons by AAV-mDLX5/6 vectors.

Publications

Preferential transduction of parvalbumin-expressing cortical neurons by AAV-mDLX5/6 vectors.

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