Abstract
Despite high enthusiasm, early attempts to develop clinical treatments based on animal research with neurotrophins were not successful. Here we survey clinical trials with neurotrophins, compared with neurotrophic factors of other gene families, and delineate the most likely reasons for their failure. We then suggest improved methods for regulated local supply of NTs to specific populations of neurons and discuss future therapeutic procedures evolving from the more detailed knowledge of the signal transduction pathways activated by neurotrophins via their receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
Levi-Montalcini, R. The nerve growth factor: thirty-five years later. EMBO J. 6, 1145–1154 (1987).
Barde, Y.-A. The nerve growth factor family. Prog. Growth Factor Res. 2, 237–348 (1990).
Bibel, M. & Barde, Y.-A. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 14, 2919–2937 (2000).
Kaplan, D.R. & Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000).
Sofroniew, M.V., Howe, C.L. & Mobley, W.C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281 (2001).
Hempstead, B.L. The many faces of p75 (NTR). Curr. Opin. Neurobiol. 12, 260–267 (2002).
Donovan, M.J. et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 127, 4531–4540 (2000).
Kerschensteiner, M., Stadelmann, C., Dechant, G., Wekerle, H. & Hohlfeld, R. Neurotrophic cross-talk between the nervous and immune systems: implications for inflammatory and degenerative neurological diseases. Ann. Neurol. (in press).
Hefti, F. & Weiner, W.J. Nerve growth factor and Alzheimer's disease. Ann. Neurol. 20, 275–281 (1986).
Fisher, W. et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329, 65–68 (1987).
Lindsay, R.M., Wiegand, S.J., Altar, C.A. & DiStefano, P.S. Neurotrophic factors: from molecule to man. Trends Neurosci. 17, 182–190 (1994).
Sendtner, M., Holtmann, B. & Hughes, R.A. The response of motoneurons to neurotrophins. Neurochem. Res. 21, 831–841 (1996).
Sendtner, M. et al. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature 358, 502–504 (1992).
Mitsumoto, H. et al. Arrests of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265, 1107–1110 (1994).
Dittrich, F. et al. Pharmacokinetics of intrathecally apllied BDNF and effects on spinal motoneurons. Exp. Neurol. 141, 225–239 (1996).
Knusel, B. et al. Ligand-induced down-regulation of trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 78, 851–862 (1997).
Thoenen, H. in Axonal Regeneration in the Central Nervous System (eds. Ingoglia, N.A. & Murray, M.) 675–697 (Marcel Dekker, New York and Basel, 2000).
McAllister, A.K., Katz, L.C. & Lo, D.C. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22, 295–318 (1999).
Zhang, L.I. & Poo, M.-M. Electrical activity and development of neural circuits. Nat. Neurosci. 4 (Suppl), 1207–1214 (2001).
Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145 (2000).
Binder, D.K., Croll, S.D., Gall, C.M. & Scharfman, H.E. BDNF and epilepsy: too much of a good thing? Trends Neurosci. 24, 47–53 (2001).
Lowenstein, P.R. & Enquist, L.W. Protocols for Gene Transfer in Neuroscience (Wiley, Chichester, UK, 1996).
Gravel, C., Gotz, R., Lorrain, A. & Sendtner, M. Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat. Med. 3, 765–770 (1997).
Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767–773 (2000).
Rossi, F.M.V. & Blau, H.M. Recent advances in inducible gene expression systems. Curr. Opin. Biotechnol. 9, 451–456 (1998).
Mansuy, I.M. & Bujard, H. Tetracycline-regulated gene expression in the brain. Curr. Opin. Neurobiol. 10, 593–596 (2000).
McKay, R. Stem cells—hype and hope. Nature 406, 361–364 (2000).
Huang, Z.J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).
Cotman, C.W. & Berchtold, N.C. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295–301 (2002).
Carro, E., Nuñez, A., Busiguina, S. & Torres-Aleman, I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. J. Neurosci. 20, 2926–2933 (2000).
Carro, E., Trejo, J.L., Busiguina, S. & Torres-Aleman, I. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J. Neurosci. 21, 5678–5684 (2001).
Baekelandt, V., De Strooper, B., Nuttin, B. & Debyser, Z. Gene therapeutic strategies for neurodegenerative diseases. Curr. Opin. Mol. Ther. 2, 540–554 (2000).
Vigna, E. et al. Robust and efficient regulation of transgene expression in vivo by improved tetracycline-dependent lentiviral vectors. Mol. Therapy 5, 252–261 (2002).
Cheng, L., Saphieha, P., Kittlerova, P., Hauswirth, W.W. & Di Polo, A. TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J. Neurosci. 22, 3977–3986 (2002).
Lee, F.S., Rajagopal, R. & Chao, M.V. Distinctive features of Trk neurotrophins receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev. 13, 11–17 (2002).
Hefti, F. Pharmacology of neurotrophic factors. Annu. Rev. Pharmacol. 37, 239–267 (1997).
Swain, C., Harper, S., Polack, S., Smith, R. & Hefti, F. in Handbook of Experimental Pharmacology (ed. Hefti, F.) 281–309 (Springer Verlag, Heidelberg/Berlin, 1999).
Venters, H.D., Dantzer, R. & Kelley, K.W. A new concept in neurodegeneration: TNF-alpha is a silencer of survival signals. Trends Neurosci. 23, 175–180 (2000).
The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. Clin. Neuropharmacol. 18, 515–532 (1995).
Miller, R.G. et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neurol. 39, 256–260 (1996).
ALS CNTF Treatment Study group (ACTS). A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 46, 1244–1249 (1996).
Aebischer, P. et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat. Med. 2, 696–699 (1996).
Penn, R.D. Kroin, J.S., York, M.M. & Cedarbaum, J.M. Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 40, 94–99 (1997).
Bachoud-Levi, A.C. et al. Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum. Gene Ther. 11, 1723–1729 (2000).
Ericsdotter Jönhagen, M. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dementia Geriatr. Cogn. Disord. 9, 246–257 (1998).
Apfel, S.C. et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 51, 695–702 (1998).
Apfel, S.C. et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. rhNGF Clinical Investigator Group. JAMA 284, 2215–2221 (2000).
McArthur, J.C. et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 54, 1080–1088 (2000).
Schifitto, G. et al. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 57, 1313–1316 (2001).
A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 52, 1427–1433 (1999).
Ochs, G. et al. A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 201–206 (2000).
Wellmer, A., Misra, V.P., Sharief, M.K., Kopelman, P.G. & Anand, P. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J. Peripher. Nerv. Syst. 6, 204–210 (2001).
Chaudhry, V. et al. Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects. Muscle Nerve 23, 189–192 (2000).
Lai, E.C. et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology 49, 1621–1630 (1997).
Borasio, G.D. et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology 51, 583–586 (1998).
Acknowledgements
We would like to thank M. Korte for critical reading of the manuscript. This research was supported by the Max-Planck Society, the Deutsche Forschungsgemeinschaft and the Hermann and Lilly Schilling Stiftung.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thoenen, H., Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat Neurosci 5 (Suppl 11), 1046–1050 (2002). https://doi.org/10.1038/nn938
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn938
This article is cited by
-
Current progression in application of extracellular vesicles in central nervous system diseases
European Journal of Medical Research (2024)
-
Osteopontin enhances the effect of treadmill training and promotes functional recovery after spinal cord injury
Molecular Biomedicine (2023)
-
Treating Parkinson's Disease via Activation of BDNF/TrkB Signaling Pathways and Inhibition of Delta-Secretase
Neurotherapeutics (2022)
-
7,8-dihydroxyflavone ameliorates motor deficits via regulating autophagy in MPTP-induced mouse model of Parkinson’s disease
Cell Death Discovery (2021)
-
Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression
Scientific Reports (2021)