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  • Review Article
  • Published:

Therapeutic interventions after spinal cord injury

Nature Reviews Neuroscience volume 7, pages 628–643 (2006)Cite this article

A Corrigendum to this article was published on 01 November 2006

Key Points

  • Spinal cord injury (SCI) can lead to paraplegia or quadriplegia and is a devastating condition for which there is as yet no cure. Cellular and molecular, as well as rehabilitative training, therapies are being developed in animal models, and some are now in, or moving towards, clinical trials.

  • Cellular therapeutic interventions after SCI include transplantation of peripheral nerve cells, Schwann cells, cells from the olfactory nervous system, stem/progenitor cells and activated macrophages.

  • Molecular therapeutic interventions after SCI include neuroprotective therapies, axonal conduction enhancement, growth factor delivery, cyclic AMP delivery, small GTPase delivery, and therapies that modulate interactions with myelin inhibitors and extracellular matrix modifiers.

  • Some of these interventions are still at the animal experimental stage. However, there are interventions that are progressing to potential application in humans through the use of human cells in animal models (for example, transplantation of Schwann cells, and stem/progenitor cells). Some therapies are already in clinical trials to treat other diseases (for example, administration of nerve growth factor in the treatment of Alzheimer's disease).

  • Other potential therapies are already in, or progressing towards, clinical trials, including transplantation of cells from the olfactory nervous system, bone marrow stromal cells and activated macrophages. The potential of 4-aminopyridine, Cethrin and Nogo-A antibodies is also being tested.

  • Improved locomotor function can be achieved with rehabilitation, because the spinal circuitry below the lesion site maintains active and functional neuronal properties, such that it can generate oscillating, coordinated motor patterns and is capable of considerable plasticity. Many SCI clinical trials are currently addressing aspects of rehabilitation, including upper-extremity exercise, body-weight-supported treadmill training and/or functional electric stimulation.

  • However, much work remains to be done to determine whether any of these therapies can safely improve outcome after human SCI. To identify therapies that are unambiguously safe and effective, the scientific and clinical SCI communities increasingly recommend that preclinical studies should be reproduced by independent laboratories. Finally, individual therapies are unlikely to emerge as a sole cure. Rather, we predict that combinations of strategies will lead to collective improvement in outcome after SCI.

Abstract

Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.

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Figure 1: Intact spinal cord.
Figure 2: Spinal cord after injury.
Figure 3: Injured spinal cord after combination treatments.
Figure 4: The olfactory nervous system.
Figure 5: Potential sources of stem/progenitor cells for transplantation into the injured spinal cord.

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Acknowledgements

We thank the Christopher Reeve Foundation and the members of their International Research Consortium. S.T. and L.D.F.M. were Associate members of this Consortium while working in the laboratories of F.H.G. and M. B. Bunge, respectively. We also thank M. L. Gage for editing the manuscript. Discussion of potential therapies in this review does not constitute endorsement by the authors.

Author information

Author notes

  1. Sandrine Thuret and Lawrence D. F. Moon: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, P.0. Box 39, 1–2 WW Ground, Denmark Hill, London, SE5 8AF, UK

    Sandrine Thuret

  2. Wolfson Centre for Age-Related Diseases, King's College London, 16–18 Newcomen Street, London, SE1 1UL, UK

    Lawrence D. F. Moon

  3. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, 92109, California, USA

    Fred H. Gage

Authors
  1. Sandrine Thuret
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Corresponding author

Correspondence to Fred H. Gage.

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Competing interests

F.G. is a member of the Scientific Advisory Boards of and holds stock in: Ceregene, Inc., Stem Cells, Inc. and Brain Cells, Inc. S.T. and L.M. have no real or perceived competing financial interests.

Related links

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FURTHER INFORMATION

Acorda Therapeutics

American Spinal Injury Association

BioAxone Therapeutic

Christopher Reeve Foundation

Clinical Trials.gov

Foundation for Spinal Cord Injury Prevention, Care and Cure

International Campaign for Cures of Spinal Cord Injury Paralysis

Miami Project to Cure Paralysis (FORE-SCI)

National Institute of Neurological Disorders and Stroke (NINDS) Facilities of Research Excellence in Spinal Cord Injury

Neuraxo Biopharmaceuticals

NINDS workshop on translating promising strategies for spinal cord injury therapy

Proneuron

Reeve–Irvine Research Centre, University of California, Irvine (FORE-SCI)

Seikagaku Corporation

Glossary

Autonomic dysreflexia

A life-threatening condition defined as a sudden and severe increase in blood pressure and a simultaneous decrease in heart rate induced by a noxious stimulus below the level of injury. Individuals with an injury at T6 or above are at risk of developing this condition.

Apoptosis

Controlled cell death, regulated by an intracellular programme of events.

Trabeculae

Strands of connective tissue that project into cysts or cavities.

Plasticity

Refers to adaptive changes in neurological function. The substrate could be anatomical (for example, collateral sprouting) or physiological (for example, changes in balance between inhibitory and excitatory transmission).

Autologous transplants

A transplant is autologous if the recipient also serves as the donor.

Olfactory lamina propria

A thick vascularized layer of connective tissue beneath the olfactory epithelium that contains nerve fibres wrapped by ensheathing glia.

Phase I clinical trial

A clinical trial that includes a small number of human participants to determine the safety of a new drug or invasive medical device; allows the determination of drug dosage or toxicity limits.

Phase II clinical trial

A clinical trial that includes a larger number of human participants than a Phase I trial and is intended to evaluate the efficacy of a treatment; side effects are also monitored.

Allodynia

A type of neuropathic pain that manifests as increased sensitivity to normally innocuous stimuli.

Phase III clinical trial

A clinical trial that includes high numbers of human participants to test a treatment or drug that has been shown to be efficacious with tolerable side effects in Phase I and Phase II clinical trials.

GTPases

Small enzymes that interact with GTP, a molecule that is used as a source of cellular energy.

Chondroitin sulphate

A glycosaminoglycan that can limit the growth of axons.

NgR(310)ecto-Fc

Soluble function-blocking protein made by fusing part of the ectodomain of NgR to rat IgG1 Fc. It could act by providing a decoy, non-signalling receptor that competes for binding of myelin-associated inhibitors of axon growth.

NEP1–40

Nogo-A has two inhibitory regions; amino-Nogo and Nogo-66. NEP1–40 is a peptide derived from Nogo-66 that antagonizes stimulation of NgR1 in vitro.

Chondroitinase ABC

A bacterial enzyme that degrades chondroitin sulphate.

Functional electrical stimulation

(FES). FES involves electrophysiological stimulation of spinal cord or peripheral nerves or muscle.

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Thuret, S., Moon, L. & Gage, F. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7, 628–643 (2006). https://doi.org/10.1038/nrn1955

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