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  • Review Article
  • Published:

Viral vectors for gene delivery to the nervous system

Nature Reviews Neuroscience volume 4, pages 353–364 (2003)Cite this article

Key Points

  • The use of viral vectors to deliver genes to the nervous system shows great promise for both basic research and therapeutic applications. However, the brain presents a challenging target for gene delivery, because of its complex structure, compartmentalized functions and high sensitivity to insult. This review describes the properties of the vector types that are currently in use, to aid in their selection for specific applications.

  • The spectrum of vectors used in basic research applications surpasses the few being used in clinical trials. It comprises viruses with simple capsid virions — such as recombinant adenovirus and adeno-associated virus — and others such as retrovirus/lentivirus, alphavirus and herpes virus, in which the capsid is surrounded by a lipid bilayer envelope.

  • Delivery modalities can be grouped into those that attempt to achieve widespread gene delivery throughout the brain (global) and those that target specific cell populations (focal). Gene delivery can be achieved by direct injection of the vector or implantation of transduced cells into the brain parenchyma.

  • Visualization of gene expression is crucial for the optimization of vector design and delivery. This has been achieved using histochemical reporter enzymes, such as Escherichia coli lacZ and human alkaline phosphatase, or fluorescent proteins, such as green fluorescent protein and red fluorescent protein.

  • With a few exceptions, most virus vectors deliver genes into the nucleus of the target cell. Within the nucleus, the viral DNA can be maintained as a non-replicating extrachromosomal element, become integrated into the host-cell genome, or replicate as an extrachromosomal element.

  • Neurons have proven to be resistant to most non-viral means of transduction, and viral vectors provide an efficient means of delivering nucleic acids to allow the expression of normal or mutant proteins within cells, or to inhibit the expression of a particular protein.

  • At present, gene therapy for disorders of the central nervous system is focused on life-threatening or severely debilitating diseases, owing in part to unknown risk factors associated with virus vectors. Neurological conditions where these vectors might prove to be effective include stroke, spinal cord injury, neurodegenerative diseases, lysosomal storage diseases, brain tumours and pain.

Abstract

Our ability to manipulate the genetic constitution of the nervous system has come of age with various technologies, including virus vectors that can efficiently deliver genes to neurons and other neural cells in vitro and in vivo. These vectors allow us to monitor neurobiological functions, replace, correct, express or block expression of target genes, tag cells for fate determination, and change the physiological state of specific cell populations. The available vectors differ in their suitability for different applications, which depends on factors such as the size of the transgene, route of delivery, tropism, duration and regulation of gene expression, and side effects.

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Figure 1: Virus entry into cells.
Figure 2: Modes of gene delivery to the brain.
Figure 3: Gene transfer to the rodent nervous system using recombinant lentivirus (feline immunodeficiency virus, FIV), adeno-associated virus serotype 5 (AAV5) and herpes simplex virus (HSV) amplicon vectors.
Figure 4: Chimaeric expression of transgenes in specific cell types.

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Acknowledgements

This review is dedicated to M. Bohn, an inspiring scientist and friend. We thank H. Ismaeel for insights into uses of imaging vectors in neurobiological studies and the contribution of an image, M. L. Cortes for the contribution of an image, D. Schuback for graphical designs, C. Stein and I. Martins for assistance with tissue sections and photography, and S. McDavitt for skilled editorial preparation of this manuscript. Funding support is provided to X.O.B. by the National Institute of Neurological Disorders and Stroke, and the Ataxia Children's Project, and to B. L. D. by the National Institutes of Health and the Roy J. Carver Trust.

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Authors and Affiliations

  1. Departments of Internal Medicine, Program in Gene Therapy, Neurology, and Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Beverly L. Davidson

  2. Department of Neurology and Center for Molecular Imaging Research, and Department of Radiology, Molecular Neurogenetics Unit, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, 02129, Massachusetts, USA

    Xandra O. Breakefield

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DATABASES

OMIM

ALS

Alzheimer disease

Huntington disease

Parkinson disease

Swiss-Prot

EBNA1

enolase

GDNF

neurofilament

NGF

synapsin-1

α-synuclein

torsinA

tyrosine hydroxylase

Glossary

RETROVIRUS

An RNA virus that uses reverse transcriptase to convert its RNA into DNA.

GREEN FLUORESCENT PROTEIN

(GFP). Fluorescent protein cloned from the jellyfish Aequoria victoria. Enhanced GFP is excited at 488 nm and has an emission maximum at 510 nm.

SEROTYPE

A variety of a species (usually bacteria or virus) characterized by its antigenic properties.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.

EPENDYMAL CELLS

A layer of cells that line the ventricles of the adult brain.

PURKINJE CELLS

Inhibitory neurons in the cerebellum that use GABA (γ-aminobutyric acid) as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.

GRANULE CELLS

Small interneurons in the cerebellum that relay excitatory signals to Purkinje neurons.

MICROGLIA

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

EPISOMAL

A term that refers to a genetic unit of replication that can exist extrachromosomally.

CONCATEMER

A linear array of identical molecules that are covalently linked in tandem.

EPITOPE

An immunological determinant of an antigen.

ANTISENSE

A single-stranded RNA molecule whose sequence is complementary to that of the messenger RNA (mRNA) for a given gene. It can bind to the mRNA, thereby preventing it from being translated.

SPINE

Specialized region of the dendrite that receives synaptic inputs from other neurons.

CRE RECOMBINASE

Part of a site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, leading to excision of the intervening sequence.

FLOXED

To be flanked by loxP sites.

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Davidson, B., Breakefield, X. Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci 4, 353–364 (2003). https://doi.org/10.1038/nrn1104

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