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  • Review Article
  • Published:

Neuroprotective gene therapy against acute neurological insults

Nature Reviews Neuroscience volume 4, pages 61–69 (2003)Cite this article

Key Points

  • Acute neurological insults disrupt neuronal energy profiles and produce hyperexcitation in glutamatergic synapses. This leads to excessive synaptic glutamate accumulation and pathological accumulation of free cytosolic calcium in postsynaptic terminals. The excess calcium triggers degenerative events, including cytoskeletal degradation, collapse of mitochondrial potentials, protein misfolding, generation of reactive oxygen species (ROS) and oxidative damage.

  • The neuronal damage caused by acute insults could be targeted by gene therapy at several levels, including hyperexcitability, glutamate or calcium excess, ROS accumulation, inflammation and neurotoxicity.

  • From a clinical perspective, it might be argued that it does not matter how a transgene protects neurons, as long as it does. However, understanding the mechanisms that underlie protection will undoubtedly help to optimize the approach.

  • Does the sparing of neurons from death also spare them from dysfunction? These events can sometimes be dissociated; for example, FGF2 overexpression spares retinal photoreceptors from light-induced degeneration, but does not restore their function. In other cases, it is expected that function is more likely to be spared if cell death is halted before metabolic collapse and oxidative damage are allowed to occur.

  • It will be important to target the earliest steps of toxicity following insults. However, the adverse effects of expressing a transgene constitutively pre-insult might outweigh the benefits. An alternative approach would be to introduce an inducible vector pre–insult and induce it at the time of the insult, or to use a vector that is induced by the insult itself.

  • The next stage will be to make the transition from showing that a particular transgene can be neuroprotective, to finding out which intervention is most effective under a particular pathological circumstance.

Abstract

In recent years, there has been tremendous progress in uncovering the molecular, cellular and systemic factors that give rise to neuronal death following acute neurological insults. This has fuelled a burgeoning interest in the use of gene transfer techniques to protect neurons from such insults. This review describes these gene therapy strategies from the perspective of the biology of neuronal death, considering which steps in the cell death cascades have been successfully targeted in pre-clinical studies, and how this research might be applied to the clinic.

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Figure 1: The biology of neurotoxicity.
Figure 2: The glucose/lactate shuttle during an acute insult.
Figure 3: The time-course of three approaches for producing an efficacious and protective protein.

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Acknowledgements

Manuscript assistance was provided by E. Cheng, T. Dumas, D. Kaufer, A. Lee and H. Zhao.

Author information

Authors and Affiliations

  1. Departments of Biological Sciences, and of Neurology and Neurological Sciences, Stanford University, Gilbert Laboratory, Stanford, 94305-5020, California, USA

    Robert M. Sapolsky

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  1. Robert M. Sapolsky
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DATABASES

LocusLink

Akt

Apaf1

Bax

Bcl2

Bclxl

BDNF

calbindin

CNTF

FGF2

GDNF

Glut1

HGF

Hif1α

Hsp70

Hsp27

IAP1

IAP2

KV1.1

NAIP

NGF

NT3

SK2

TGF-β

XIAP

OMIM

Alzheimer's disease

Swiss-Prot

CrmA

p35

FURTHER INFORMATION

Encyclopedia of Life Sciences

adeno-associated viruses

adenoviruses

Alzheimer disease

apoptosis: molecular mechanisms

gene delivery by viruses

heat shock response

herpesvisuses (human)

human gene therapy

Glossary

AXOTOMY

Cutting of the axon.

APOPTOSIS

A common form of cell death, also known as 'intrinsic' or 'programmed' cell death. Many physiological and developmental stimuli cause apoptosis, and the mechanism is used frequently to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation. Apoptosis involves cell shrinkage, condensation of chromatin in the periphery of the nucleus, cell-membrane blebbing and DNA fragmentation into multiples of about 180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by a neighbouring cell.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

PARAPTOSIS

A form of programmed cell death that does not require the activation of caspases, and produces different changes in cell morphology from those that are usually associated with apoptosis.

OUTWARDLY-RECTIFYING K+ CHANNELS

Potassium channels through which ions flow more easily out of than into the cell.

AFTERHYPERPOLARIZATION

The membrane hyperpolarization that follows the occurrence of an action potential.

HEAT-SHOCK

A cellular response that is caused by exposure to a temperature that is higher than normal. The heat-shock proteins, many of which function as molecular chaperones, are synthesized in larger amounts under these conditions, and many of them are also crucial for cellular functions under non-stress conditions.

DOMINANT-NEGATIVE MUTANT

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

COMPLEMENT

The complement system is a set of plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes. Complement components are also involved in inflammation and tissue destruction.

NEUTROPHIL

 A phagocytic cell of the myeloid lineage that has an important role in the inflammatory response, undergoing chemotaxis towards sites of infection or wounding.

MOLECULAR CHAPERONE

A protein that assists in the non-covalent assembly of a protein complex but does not participate in its function.

ELECTRORETINOGRAMS

Measurements of the retinal response to light, typically using an electrode attached to the cornea.

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Sapolsky, R. Neuroprotective gene therapy against acute neurological insults. Nat Rev Neurosci 4, 61–69 (2003). https://doi.org/10.1038/nrn1006

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