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.

  • Article
  • Published:

Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors

Abstract

Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy cause progressive paralysis, often leading to premature death. Neurotrophic factors have been suggested as therapeutic agents for motor neuron diseases, but their clinical use as injected recombinant protein was limited by toxicity and/or poor bioavaiiability. We demonstrate here that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) can produce substantial therapeutic effects in the mouse mutant pmn (progressive motor neuronopathy). After intramuscular injection of the NT-3 adenoviral vector, pmn mice showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function as assessed by electromyography. These results were further improved by coinjecting an adenoviral vector coding for ciliary neurotrophic factor. Therefore, adenovirus-mediated gene transfer of neurotrophic factors offers new prospects for the treatment of motor neuron diseases.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Thoenen, H., Hughes, R.A. & Sendtner, M. Trophic support of motoneurons: Physiological, pathophysiological, and therapeutic implications. Exp. Neurol. 124, 47–55 (1993).

    Article  CAS  Google Scholar 

  2. Henderson, C.E. Neurotrophic factors as therapeutic agents in ALS. Adv. Neurol. 68, 235–240 (1995).

    CAS  PubMed  Google Scholar 

  3. Oppenheim, R.W., Prevette, D., Yin, Q.W., Collins, F. & MacDonald, J. Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science 251, 1616–1618 (1991).

    Article  CAS  Google Scholar 

  4. Oppenheim, R.W., Qin-Wei, Y., Prevette, D. & Yan, P. Brain-derived neurotrophic factor rescues avian motoneurons from Cell death. Nature 360, 755–757 (1992).

    Article  CAS  Google Scholar 

  5. Oppenheim, R.W. et al. Developing motor neurons rescued from programmed and axotomy-induced Cell death by GDNF. Nature 373, 344–346 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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 

  8. Mitsumoto, H. et al. Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265, 1107–1110 (1994).

    Article  CAS  Google Scholar 

  9. Dittrich, F., Thoenen, H. & Sendner, M. Ciliary neurotrophic factor: Pharmacokinetics and acute-phase response in rat. Ann. Neurol. 35, 151–163 (1994).

    Article  CAS  Google Scholar 

  10. Cedarbaum, J.M. et al. A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. Clin. Neuropharmacol. 18, 515–532 (1995).

    Article  CAS  Google Scholar 

  11. Miller, R.G. et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Ann. Neurol. 39, 256–260 (1996).

    Article  CAS  Google Scholar 

  12. Jaffe, H.A. et al. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver. Nature Genet. 1, 372–378 (1992).

    Article  CAS  Google Scholar 

  13. Rosenfeld, M.A. et al. Adenovirus-mediated transfer of a recombinant alpha 1-anti-trypsin gene to the lung epithelium in vivo. Science 252, 431–434 (1991).

    Article  CAS  Google Scholar 

  14. Quantin, B., Perricaudet, L.D., Tajbakhsh, S. & Mandel, J.-L. Adenovirus as an expression vector in muscle Cells in vivo. Proc. Natl. Acad. Sci. USA 89, 2581–2584 (1992).

    Article  CAS  Google Scholar 

  15. Stratford-Perricaudet, L.D., Makeh, I., Perricaudet, M. & Briand, P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J. Clin. Invest. 90, 626–630 (1992).

    Article  CAS  Google Scholar 

  16. Vincent, N. et al. Long-term correction of mouse dystrophic degeneration by adenovirus-mediated transfer of a minidystrophin gene. Nature Cenet. 5, 130–134 (1993).

    Article  CAS  Google Scholar 

  17. Akli, S. et al. Transfer of a foreign gene into the brain using adenovirus vectors. Nature Genet. 3, 224–228 (1993).

    Article  CAS  Google Scholar 

  18. Schmalbruch, H., Jensen, H.S., Bjaerg, M., Kamieniecka, Z. & Kurland, L. A new mouse mutant with progressive motor neuronopathy. J. Neuropathol. Exp. Neurol 50, 192–204 (1991).

    Article  CAS  Google Scholar 

  19. Hohn, A., Leibrock, J., Bailey, K. & Barde, Y.A. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344, 339–341 (1990).

    Article  CAS  Google Scholar 

  20. Maisonpierre, P.C. et al. Neurotrophin-3: A neurotrophic factor related to NGF and BDNF. Science 247, 1446–1451 (1990).

    Article  CAS  Google Scholar 

  21. Griesbeck, O., Parsadanian, A.S., Sendtner, M. & Thoenen, H. Expression of neurotrophins in skeletal muscle: Quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 42, 21–33 (1995).

    Article  CAS  Google Scholar 

  22. Henderson, C.E. et al. Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature 363, 266–270 (1993).

    Article  CAS  Google Scholar 

  23. Ozcelik, T., Rosenthal, A. & Francke, U. Chromosomal mapping of brain-derived neurotrophic factor and neurotrophin-23 genes in man and mouse. Genomics 10, 569–575 (1991).

    Article  CAS  Google Scholar 

  24. Brunialti, A.L.B., Poirier, C., Schmalbruch, H. & Guenet, J.L. The mouse mutation progressive motor neuronopathy (pmn) maps to chromosome 13. Genomics 29, 131–135 (1995).

    Article  CAS  Google Scholar 

  25. Johnson, D.R. Extra-toes: A new mutant gene causing multiple abnormalities in the mouse. J. Embryol. Exp. Morphol. 17, 543–581 (1967).

    CAS  PubMed  Google Scholar 

  26. Kennel, P.F. et al. Electromyographical and motor performance studies in the pmn mouse model of neurodegenerative disease. Neurobiol. Dis. 3, 137–147 (1996).

    Article  CAS  Google Scholar 

  27. Willison, R.G. Analysis of electrical activity in healthy and dystrophic muscle in man. J. Neurol. Neurosurg. Psychiatry 27, 386–394 (1964).

    Article  CAS  Google Scholar 

  28. Hansen, S. & Ballantyne, J.P. A quantitative electrophysiological study of motor neurone disease. J. Neurol. Neurosurg. Psychiatry 41, 773–783 (1978).

    Article  CAS  Google Scholar 

  29. Namba, T., Nakamura, T. & Grob, D. Staining for nerve fiber and cholinesterase activity in fresh frozen sections. Am. J. Clin. Pathol. 47, 74–77 (1967).

    Article  CAS  Google Scholar 

  30. Gurney, M.E., Yamamoto, H. & Kwon, Y. Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor. J. Neurosci. 12, 3241–3247 (1992).

    Article  CAS  Google Scholar 

  31. Sagot, Y., Tan, S.A., Hammang, J.P., Aebischer, P. & Kato, A.C. GDNF slows loss of motoneurons but not axonal degeneration or premature death of pmn/pmn mice. J. Neurosci. 16, 2335–2341 (1996).

    Article  CAS  Google Scholar 

  32. Sagot, Y. et al. Bcl-2 overexpression prevents motoneuron Cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J. Neurosci. 15, 7727–7733 (1995).

    Article  CAS  Google Scholar 

  33. Langford, L.A. & Schmidt, R.F. An electron microscopic analysis of the left phrenic nerve in the rat. Anat. Rec. 205, 207–213 (1983).

    Article  CAS  Google Scholar 

  34. Schnell, L. Schneider, R. Kolbeck, R. Barde, Y.A. & Schwab, M.E. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173 (1994).

    Article  CAS  Google Scholar 

  35. Funakoshi, H. et al. Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science 268, 1495–1499 (1995).

    Article  CAS  Google Scholar 

  36. Braun, S., Croizat, B., Lagrange, M.C., Warter, J.M. & Poindron, P. Neurotrophins increase motoneurons' ability to innervate skeletal muscle fibers in rat spinal cord-human muscle cocultures. J. Neurol. Sci. 136, 17–23 (1996).

    Article  CAS  Google Scholar 

  37. Lohof, A.M., Ip, N.Y. & Poo, M.-M. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 363, 350–353 (1993).

    Article  CAS  Google Scholar 

  38. Stoop, R. & Poo, M.-M. Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling. Science 267, 695–699 (1995).

    Article  CAS  Google Scholar 

  39. Helgren, M.E. et al. Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle. Cell 76, 493–504 (1994).

    Article  CAS  Google Scholar 

  40. Ghadge, G.D. et al. CNS gene delivery by retrograde transport of recombinant replication-defective adenoviruses. Gene Ther. 2, 132–137 (1995).

    CAS  PubMed  Google Scholar 

  41. Finiels, F. et al. Specific and efficient gene transfer strategy offers new potentialities for the treatment of motor neurone diseases. Neuroreport 7, 373–378 (1995).

    Article  CAS  Google Scholar 

  42. DiStefano, P.S. et al. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron 8, 983–993 (1992).

    Article  CAS  Google Scholar 

  43. Hitt, M., Bett, A.J., Prevec, L. & Graham, F.L. Construction and propagation of human adenovirus vectors, in Cell Biology — A Laboratory Handbook, Vol. 1 (ed. Celis, J. E.) 479–490 (Academic Press, San Diego, 1994).

    Google Scholar 

  44. Bottenstein, J.E. Skaper, S.D. Varon, S. & Sato, G. Selective survival of neurons from chick embryo sensory ganglionic dissociates using serum-free supplemented medium. Exp. Cell Res. 125, 183–190 (1980).

    Article  CAS  Google Scholar 

  45. Manthorpe, M., Fagnani, R., Skaper, S.D. & Varon, S. An automated colorimetric microassay for neurotrophic factors. Dev. Brain Res. 25, 195–198 (1986).

    Article  Google Scholar 

  46. Bischoff, C. Stålberg, E. Falck, B. & Eeg-Ologsson, K.E. Reference values of motor unit action potentials obtained with multi-MUP analysis. Muscle Nerve 17, 842–851 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haase, G., Kennel, P., Pettmann, B. et al. Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nat Med 3, 429–436 (1997). https://doi.org/10.1038/nm0497-429

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0497-429

This article is cited by

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