Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease

Nature volume 386, pages 395–399 (1997)Cite this article

Abstract

Huntington's disease is a genetic disorder that results from degeneration of striatal neurons, particularly those containing GABA (γ-aminobutyric acid)1. There is no effective treatment for preventing or slowing this neuronal degeneration. Ciliary neurotrophic factor (CNTF) is a trophic factor for striatal neurons2,3 and therefore a potential therapeutic agent for Huntington's disease. Here we evaluate CNTF as a neuroprotective agent in a non-human primate model of Huntington's disease. We gave cyno-molgus monkeys intrastriatal implants of polymer-encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unilateral injections of quinolinic acid into the previously implanted striatum to reproduce the neuropathology seen in Huntington's disease4,5. Human CNTF was found to exert a neuroprotective effect on several populations of striatal cells, including GABAergic, cholinergic and diaphorase-positive neurons which were all destined to die following administration of quinolinic acid. Human CNTF also prevented the retrograde atrophy of layer V neurons in motor cortex and exerted a significant protective effect on the GABAergic innervation of the two important target fields of the striatal output neurons (the globus pallidus and pars reticulata of the substantia nigra). Our results show that human CNTF has a trophic influence on degenerating striatal neurons as well as on critical non-striatal regions such as the cerebral cortex, supporting the idea that human CNTF may help to prevent the degeneration of vulnerable striatal populations and cortical–striatal basal ganglia circuits in Huntington's disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Reiner, A. et al. Differential loss of striatal projection neurons in Huntington's disease. Proc. Natl Acad. Sri. USA 85, 5733–5737 (1988).

    Article  ADS  CAS  Google Scholar 

  2. Anderson, K. D., Panayotatos, N., Cordoran, T. L., Lindsay, R. M. & Wiegand, S. J. Ciliary neurotroophic factor protects striatal output neurons in an animal model of Huntington's disease. Proc. Natl Acad. Sci. USA 93, 7346–7351 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Emerich, D. F. et al. Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. J. Neurosci. 16, 5168–5181 (1996).

    Article  CAS  Google Scholar 

  4. Beal, M. F. et al. Replication of the neurochemical characteristics Huntington's disease by quinolinic acid. Nature 32l, 168–171 (1986).

    Article  ADS  Google Scholar 

  5. Beal, M. F., Kowall, N. W., Swartz, K. J., Ferranti, R. J. & Martin, J. B. Differential sparing of somatostatin-neuropeptide Y and cholinergic neurons following striatal excitotoxin lesions. Synapse 3, 38–47 (1989).

    Article  CAS  Google Scholar 

  6. Emerich, D. F. & Sanberg, P. R. in Neuromethods: Animal Models of Neurological Disease (eds Boulton, A. A., Baker, G. B. & Butterworth, R. F.) Vol. 17, 65–134 (Humana, New Jersey, 1992).

    Book  Google Scholar 

  7. Ferrante, R. J., Beal, M. F., Kowall, N. W., Richardson, E. P. & Martin, J. B. Sparing of acetylcholi-nesterase-containing striatal neurons in Huntington's disease. Brain Res. 415, 178–182 (1987).

    Article  Google Scholar 

  8. Roberts, R. C. & DiFiglia, M. Short- and long-term survival of large nurons in the excitotoxic lesioned rat caudate nucleus: a light and electron microscopic study. Synapse 3, 363–371 (1989).

    Article  CAS  Google Scholar 

  9. Albin, R. L. & Greenamyre, J. T. Alternative excitotoxic hypothesis. Neurology 42, 733–738 (1992).

    Article  CAS  Google Scholar 

  10. Beal, M. F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neural. 31, 119–130 (1992).

    Article  CAS  Google Scholar 

  11. Parker, W. D., Boyson, S. J., Luder, A. S. & Parks, J. K. Evidence for a defect on NADH:ubiquinone oxidoreductase (complex I) in Huntington's disease. Neurology 40, 1231–1234 (1990).

    Article  Google Scholar 

  12. Wallace, D. C. W Mitochondrial genetics: A paradigm for aging and degenerative diseases? Science 256, 628–632 (1992).

    Article  ADS  CAS  Google Scholar 

  13. Apfel, S. C., Arezzo, J. C., Moran, M. & Kessler, J. A. Effects of administration of ciliary neurotrophic factor on normal motor and sensory peripheral nerves in vivo. Brain Res. 604, 1–6 (1993).

    Article  CAS  Google Scholar 

  14. Sagot, Y. et al. Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse. Eur. J. Neurosci. 7, 1313–1322 (1995).

    Article  CAS  Google Scholar 

  15. Sendtner, M. et al. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronpathy. Nature 358, 502–504 (1992).

    Article  ADS  CAS  Google Scholar 

  16. Clatterbuck, R. E., Price, D. L. & Koliatsos, V. E. Ciliary neurotrophic factor prevents retrograde neuronal death in the adult central nervous system. Proc. Natl Acad. Sci. USA 90, 2222–2226 (1993).

    Article  ADS  CAS  Google Scholar 

  17. Hagg, T., Quon, D., Higaki, J. & Varon, S. Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS. Neuron 8, 145–158 (1993).

    Article  Google Scholar 

  18. Hagg, T. & Varon, S. Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo. Proc. Natl Acad. Sci. USA 90, 6315–6319 (1993).

    Article  ADS  CAS  Google Scholar 

  19. Emerich, D. F., Hammang, J. P., Baetge, E. E. & Winn, S. R. Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum. Exper. Neurol. 130, 141–150 (1994).

    Article  CAS  Google Scholar 

  20. Frim, D. M. et al. Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions. Neuroreport 4, 67–370 (1993).

    Google Scholar 

  21. Frim, D. M. et al. Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF. J. Neurosci. Res. 35, 452–458 (1993).

    Article  CAS  Google Scholar 

  22. Schumacher, J. M., Short, M. P., Hyman, B. T., Breakefiled, X. O. & Isacson, O. Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience 45, 561–70 (1991).

    Article  CAS  Google Scholar 

  23. Tulipan, N., Luo, S.-Q., Allen, G. & Whetsell, W. O. Striatal grafts provide sustained protection from kainic and quinolinic acid-induced damage. Exp. Neurol. 102, 325–332 (1988).

    Article  CAS  Google Scholar 

  24. Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988).

    Article  CAS  Google Scholar 

  25. Olney, J. W. Excitatory amino acids and neuropsychiatric disorders. Biol. Psychiatr. 26, 505–525 (1989).

    Article  CAS  Google Scholar 

  26. Baetge, E. E., Suh, Y. H. & Joh, T. H. Complete nucleotide and decuced amino acid sequence of bovine phenylethanolamine N-methyltransferase: partial homology with rat tyrosine hydroxylase. Proc. Natl Acad. Sci. USA 83, 5454–5458 (1986).

    Article  ADS  CAS  Google Scholar 

  27. Winn, S. R. et al. Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons. Proc. Natl Acad. Sci. USA 91, 23–28 (1994).

    Article  Google Scholar 

  28. Emerich, D. F. et al. Transplantation of polymer-encapsulated cells genetically modified to secrete human nerve growth factor prevents the loss of degenerating cholinergic neurons in nonhuman primates. J. Comp. Neurol. 349, 148–164 (1994).

    Article  CAS  Google Scholar 

  29. Kordower, J. H., Chen, E.-Y., Mufson, E. J., Winn, S. R. & Emerich, D. F. Intrastriatal implants of polymer-encapsulated cells genetically modified to secrete human NGF: trophic effects upon cholinergic and noncholinergic neurons. Neuroscience 72, 63–77 (1996).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Dwaine F. Emerich

    Present address: Alkermes, Inc., 64 Sidney Street, Cambridge, Massachusetts, 02139, USA

Authors and Affiliations

  1. CytoTherapeutics Inc., Providence, Rhode Island, 02906, USA

    Dwaine F. Emerich, Patricia McDermott & E. Edward Baetge

  2. Department of Surgery, Oregon Health Sciences University, Portland, Oregon, 97201, USA

    Shelley R. Winn

  3. URA CNRS 1285, Svc Hosp Frederic Joliet, 4 Place Gen Leclerc, Orsay, 91406, France

    Philippe M. Hantraye

  4. INSERM U421, Fac De Medicine, F94010, Creteil Cedex, France

    Marc Peschanski

  5. Research Center for Brain Repair and Department of Neurological Sciences, Rush Presbyterian–St Luke's Medical Center, Chicago, Illinois, 60612, USA

    Er-Yun Chen, Yaping Chu & Jeffrey H. Kordower

Authors
  1. Dwaine F. Emerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shelley R. Winn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe M. Hantraye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Peschanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Er-Yun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaping Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia McDermott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. Edward Baetge
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey H. Kordower
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Emerich, D., Winn, S., Hantraye, P. et al. Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease. Nature 386, 395–399 (1997). https://doi.org/10.1038/386395a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/386395a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing