Viral Vectors and Delivery Strategies for CNS Gene Therapy

Gray, Steven J.; Woodard, Kenton; Samulski, R. Jude

doi:10.4155/tde.10.50

Cited by 109 publications

(76 citation statements)

References 131 publications

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“…Additionally, when used in transgenic lines, viral gene delivery further expands the capacity to express different molecules in neuron subtypes. A major challenge in developing viral gene delivery tools is the limited DNA packaging capacity of the most commonly used viral vectors, lentivirus (LV) and adeno-associated virus (AAV) (Gray et al, 2010; Blessing and Déglon, 2016). Thus, the use of cell-type-specific promoter and enhancer elements for viral gene delivery has been mainly limited to a few neuron types, as the large size and the complexity of these natural elements often leads to complications with viral packaging or transgene expression (Dittgen et al, 2004; Nathanson, et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex

Keaveney

Tseng

et al. 2018

Cell Reports

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In Brief Viral targeting of neuron subtypes is desirable for neuroscience research. Keaveney et al. developed a microRNA-based viral tool for labeling cortical interneurons. They demonstrate its utility via neuron subtype labeling in a murine disease model and in rats and through dual-color optogenetic control of two neuron types. SUMMARY More specific and broadly applicable viral gene-targeting tools for labeling neuron subtypes are needed to advance neuroscience research, especially in rodent transgenic disease models and genetically intractable species. Here, we develop a viral vector that restricts transgene expression to GABAergic interneurons in the rodent neocortex by exploiting endogenous microRNA regulation. Our interneurontargeting, microRNA-guided neuron tag, ‘‘GABA mAGNET,’’ achieves >95% interneuron selective labeling in the mouse cortex, including in a murine model of autism and also some preferential labeling of interneurons in the rat brain. We demonstrate an application of our GABA mAGNET by performing simultaneous, in vivo optogenetic control of two distinct neuron subtypes. This interneuron labeling tool highlights the potential of microRNA-based viral gene targeting to specific neuron subtypes.

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Section: Introductionmentioning

confidence: 99%

A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex

Keaveney

Tseng

et al. 2018

Cell Reports

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“…A total of 1843 gene therapy clinical trials have been initiated (current as of 2012) (Ginn, Alexander, Edelstein, Abedi, & Wixon, 2013). Of gene therapy clinical trials (including plasmid DNA) registered from 2000 to 2012 that focus on neurological disorders, 48% use an AAV vector delivery system, notably including Parkinson's disease (PD) and late infantile neuronal ceriod lipofuscinosis (Batten disease) (http://www.wiley.com//legacy/wileychi/genmed/clinical/) (Gray, Woodard, & Samulski, 2010). …”

Section: Introductionmentioning

confidence: 99%

Clinical Applications Involving CNS Gene Transfer

Kantor

McCown

Leone

et al. 2014

Advances in Genetics

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Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors.

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“…Utilizing knowledge gained from naturally occurring serotypes and mosaic capsids, researchers are now able to engineer rAAV capsids to enhance tissue selectivity and specificity as well as to evade host neutralizing antibodies. Second-generation AAV vectors are generated through methods including (1) rational design based on known AAV structure and biology, (2) use of directed evolution through mutagenesis and DNA shuffling, and (3) peptide insertion of ligands into the AAV capsid (reviewed in Gray, Woodard, and Samulski, (2010)). Together, these newly engineered AAV vectors offer a broad range of selection to meet different experimental and therapeutic needs.…”

Section: Vectors For Cns Gene Transfermentioning

confidence: 99%

Methods for Gene Transfer to the Central Nervous System

Kantor

Bailey

Wimberly

et al. 2014

Advances in Genetics

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Gene transfer is an increasingly utilized approach for research and clinical applications involving the central nervous system (CNS). Vectors for gene transfer can be as simple as an unmodified plasmid, but more commonly involve complex modifications to viruses to make them suitable gene delivery vehicles. This chapter will explain how tools for CNS gene transfer have been derived from naturally occurring viruses. The current capabilities of plasmid, retroviral, adeno-associated virus, adenovirus, and herpes simplex virus vectors for CNS gene delivery will be described. These include both focal and global CNS gene transfer strategies, with short- or long-term gene expression. As is described in this chapter, an important aspect of any vector is the cis-acting regulatory elements incorporated into the vector genome that control when, where, and how the transgene is expressed.

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Viral Vectors and Delivery Strategies for CNS Gene Therapy

Cited by 109 publications

References 131 publications

A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex

A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex

Clinical Applications Involving CNS Gene Transfer

Methods for Gene Transfer to the Central Nervous System

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