Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons

Abstract

The neurotrophic factors ciliary neurotrophic factor and brainderived neurotrophic factor can prevent motor neuron cell death during development1,2 and after nerve lesion in neonatal rodents3,4. However, local and systemic application of these factors to newborn rats with damaged motor nerves rescues motor neurons only transiently during the first two weeks after axotomy5,6. In order to test the effect of continuous delivery of these factors, the effect of localized injection of CNTF- or BDNF-transducing recombinant adenoviruses into the lesioned nerves was investigated. Under such conditions, survival of axotomized motor neurons is maintained for at least 5 weeks. This way of delivery corresponds to the physiological situation in adult rodents, under which endogenous CNTF is present in the cytosol of Schwann cells and BDNF expression is upregulated after nerve lesion, making these factors available to the damaged motor neurons7,8. Recent results show that overexpression of muscle-derived neurotrophin-3 prevents degeneration of axons and motor endplates, but has only little effect on the number of motor neuron cell bodies in a murine animal model of motor neuron disease9. Therefore, techniques suitable for tonic exposure to both nerve- and muscle-derived neurotrophic factors may have implications for the design of future therapeutic strategies against human motor neuron disease.

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References

  1. 1

    Oppenheim, R.W., Prevette, D., Qin-Wei, Y., Collins, F. & MacDonald J. Control of embryonic motor neuron survival in vivo by ciliary neurotrophic factor. Science 251, 1616–1618 (1991).

  2. 2

    Oppenheim, R.W., Qin-Wei, Y., Prevette, D. & Yan, Q. Brain-derived neurotrophic factor rescues developing avian motor neurons from cell death. Nature 360, 755–757 (1992).

  3. 3

    Sendtner, M., Kreutzberg, G.W. & Thoenen, H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345, 440–441 (1990).

  4. 4

    Sendtner, M., Holtmann, B., Kolbeck, R., Thoenen, H. & Barde, Y.-A. Brain-derived neurotrophic factor prevents the death of motor neurons in newborn rats after nerve section. Nature 360, 757–758 (1992).

  5. 5

    Eriksson, N.P., Lindsay, R.M. & Aldskogius, H. BDNF and NT-3 rescue sensory but not motoneurones following axotomy in the neonate. Neuroreport 5, 1445–1448 (1994).

  6. 6

    Vejsada, R., Sagot, Y. & Kato, A.C. Quantitative comparison of the transient rescue effects of neurotrophic factors on axotomized motor neurons in vivo. Eur. J. Neurosci. 7, 108–115 (1995).

  7. 7

    Sendtner, M., Stöckli, K.A. & Thoenen, H. Synthesis and location of ciliary neurotrophic factor in the rat sciatic nerve of the adult rat after lesion and during regeneration. J. Cell Biol. 118, 139–148 (1992).

  8. 8

    Meyer, M., Matsuoka, I., Wetmore, C., Olson, L. & Thoenen, H. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: Different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J. Cell Biol. 119, 45–54 (1992).

  9. 9

    Haase, G. et al. Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nature Med. 3, 429–436 (1997).

  10. 10

    Oppenheim, R.W. Naturally occurring cell death during neural development. Trends Neurosci. 8, 487–493 (1985).

  11. 11

    Yan, Q. et al. Influences of neurotrophins on mammalian motor neurons in vivo. J. Neurobiol. 24, 1555–1577 (1993).

  12. 12

    Hirano, A. & Iwata, M. Pathology of motor neurons with special reference to amyotrophic lateral sclerosis and related diseases. in: Amyotrophic Lateral Sclerosis. (eds. Tsubaki, T. & Toyokura, Y.) 107–134 (University Park Press, Baltimore, 1979).

  13. 13

    Schmalbruch, H. Motor neuron death after sciatic nerve section in newborn rats. J. Comp. Neurol. 224, 252–258 (1984).

  14. 14

    Hughes, R.A., Sendtner, M. & Thoenen, H. Members of several gene families influence survival of rat motor neurons in vitro and in vivo. J. Neurosci. Res. 36, 663–671 (1993).

  15. 15

    Henderson, C.E. et al. GDNF: A potent survival factor for motor neurons present in peripheral nerve and muscle. Science 266, 1062–1064 (1994).

  16. 16

    Yan, Q., Elliott, J. & Snider, W.D. Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360, 753–755 (1992).

  17. 17

    Koliatsos, V.E. et al. Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons. Proc. Natl. Acad. Sci. USA 91, 3304–3308 (1994).

  18. 18

    Yan, Q., Matheson, C. & Lopez, O.T. In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature 373, 341–344 (1995).

  19. 19

    Martinou, J.C., Martinou, I. & Kato, A. Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motor neurons in vitro. Neuron 8, 737–744 (1992).

  20. 20

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

  21. 21

    Ikeda, K. et al. Effects of brain-derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann. Neurol. 37, 505–511 (1995).

  22. 22

    Mitsumoto, H. et al. The effects of ciliary neurotrophic factor on motor neuron dysfunction in wobbler mouse motor neuron disease. Ann. Neurol. 36, 142–148 (1994).

  23. 23

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

  24. 24

    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).

  25. 25

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

  26. 26

    ALS CNTF Treatment Study (ACTS) Phase l-ll Group.The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. Clin. Neuropharmacol. 18, 500–518 (1995).

  27. 27

    Vejsada, R., Sagot, Y. & Kato, A.C. BDNF-mediated rescue of axotomized motor neurones decreases with increasing dose. Neuroreport 5, 1889–1892 (1994).

  28. 28

    Carter, B.D., Zirrgiebel, U. & Barde, Y.A. Differential regulation of p21ras activation in neurons by nerve growth factor and brain-derived neurotrophic factor. J. Biol. Chem. 270, 21751–21757 (1995).

  29. 29

    Yan, Q., Matheson, C. Lopez, O.T. & Miller, J.A. The biological responses of axotomized adult motor neurons to brain-derived neurotrophic factor. J. Neurosci. 14, 5281–5291 (1994).

  30. 30

    Dittrich, F. et al. Pharmacokinetics of intrathecally applied BDNF and effects on spinal motor neurons. Exp. Neurol. 141, 225–239 (1996).

  31. 31

    Stöckli, K.A. et al. Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature 342, 920–923 (1989).

  32. 32

    Stöckli, K.A. et al. Regional distribution, developmental changes and cellular localization of CNTF-mRNA and protein in the rat brain. J. Cell Biol. 115, 447–459 (1991).

  33. 33

    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).

  34. 34

    Jones, N. & Schenk, T. Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell 17, 683–689 (1979).

  35. 35

    Vilquin, J.-T. et al. FK 506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. Hum. Gene Ther. 6, 1391–1401 (1995).

  36. 36

    Masu, Y. et al. Disruption of the CNTF gene results in motor neuron degeneration. Nature 365, 27–32 (1993).

  37. 37

    Le Gal La Salle, G. et al. An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259, 988–990 (1993).

  38. 38

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

  39. 39

    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).

  40. 40

    Tripathy, K.S., Hugh, B.B., Goldwasser, E. & Leiden J.M. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nature Med. 2, 545–550 (1996).

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