Nerve growth factor for the treatment of diabetic neuropathy: What went wrong, what went right, and what does the future hold?

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Abstract

Since their discovery in the 1950s, neurotrophic factors have raised expectations that their clinical application to neurodegenerative diseases might provide an effective therapy for what are now untreatable conditions. Nerve growth factor (NGF) was the first neurotrophic factor to be discovered and was one of the earliest to proceed to clinical trials. NGF, which is selectively trophic for small fiber sensory and sympathetic neurons, was selected as a potential therapy for diabetic polyneuropathy because of the serious consequences associated with degeneration of those neuronal populations in this condition. In addition, evidence shows that reduced availability of NGF may contribute to the pathogenesis of diabetic neuropathy, and animal models of neuropathy respond to the exogenous administration of NGF. Two sets of phase II clinical trials suggested that recombinant human NGF (rhNGF) administration was effective at ameliorating the symptoms associated with both diabetic polyneuropathy and HIV related neuropathy. These early studies, however, revealed that painful side effects were dose limiting for NGF. A large-scale phase III clinical trial of 1019 patients randomized to receive either rhNGF or placebo for 48 weeks failed to confirm the earlier indications of efficacy. Among the explanations offered for the discrepancy between the two sets of trials was a robust placebo effect, inadequate dosage, different study populations, and changes to the formation of rhNGF for the phase III trial. As a result of the phase II outcome, Genentech has decided no to proceed with further development of rhNGF.

References (39)

  • R Klein et al.

    The trk B tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3

    Cell

    (1991)
  • P.N.M Konings et al.

    Reversal by NGF of cytostatic drug reduction of neurite outgrowth in dorsal root ganglia in vitro

    Brain Res.

    (1994)
  • F Lamballe et al.

    Trk C, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3

    Cell

    (1991)
  • G Ordonez et al.

    Low contents of nerve growth factor in serum and submaxillary gland of diabetic mice: A possible etiological element of diabetic neuropathy

    J Neurol. Sci.

    (1994)
  • K Ren et al.

    Nerve growth factor alleviates a painful peripheral neuropathy in rats

    Brain Res.

    (1995)
  • L.S Ro et al.

    Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve

    Pain

    (1999)
  • P Anand et al.

    The role of endogenous nerve growth factor in human diabetic neuropathy

    Nature Med.

    (1996)
  • S.C Apfel et al.

    Nerve growth factor prevents experimental cisplatin neuropathy

    Ann. Neurol.

    (1992)
  • S.C Apfel et al.

    Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy

    Neurology

    (1998)
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