The clinical results of the use of neurotrophic factors in peripheral neuropathies are shown in Table 2 and described in the following text.
Table 2. Neurotrophic Factors and Similar Drugs in Development for Peripheral Neuropathies
III. Insulin-like growth factor
IV. Neurotrophin-3 receptor-agonist monoclonal antibodies
V. Recombinant human nerve growth factor
VI. Brain-derived neurotrophic factor
Delivery of neurotrophic factors. Delivery of neurotrophic factors to the peripheral nerves is easier than delivery to the brain. Although neurotrophic factors can be injected locally, cell and gene therapies provide targeted and safer delivery.
Gene transfer using herpes virus vectors to target delivery of neurotrophic factors to the primary sensory afferent for treatment of neuropathy resulting from diabetes or use of anticancer drugs provides highly selective targeted release of bioactive molecules within the peripheral nervous system (Wolfe et al 2012). Preclinical studies with nonreplicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in preventing progression of sensory neuropathy (Chattopadhyay 2013).
Bone marrow-derived cells such as mononuclear cells or endothelial progenitor cells can produce neurotrophic factors and have been used for treating experimental diabetic neuropathy with reversal of manifestations of the disease (Kim et al 2012).
Diabetic neuropathy. Neurotrophic factors and drugs with neurotrophic activity used for the treatment of diabetic neuropathy are as follows:
Gangliosides. Open studies of use of gangliosides in patients with various types of neuropathies have reported relief of sensory symptoms and motor deficits, but no controlled trial has been carried out.
Nerve growth factor. The efficacy of intradermal recombinant human nerve growth factor in inducing pressure allodynia and lowering heat-pain threshold in healthy human volunteers has been demonstrated. The onset of action was too rapid to be explained by uptake of nerve growth factor by nociceptive terminals, retrograde transport, and up-regulation of pain modulators. Local mechanisms were implicated in this effect.
Development of nerve growth factor for diabetic neuropathy was discontinued because phase 3 results did not confirm efficacy.
Neurotrophin-3. As a neurotrophin similar to brain-derived neurotrophic factor, neurotrophin-3 is a candidate for clinical trials in diabetic neuropathy. A double-blind, placebo-controlled clinical trial testing the safety and tolerability of neurotrophin-3 in diabetic patients was conducted at 5 clinical sites, 4 in the United States and 1 in Canada. From the available evidence it appears that neurotrophin-3 is likely to be the best neurotrophic factor for the treatment of diabetic neuropathy where sensory and autonomic dysfunction is involved. When combined with brain-derived neurotrophic factors, it can cover the entire spectrum of types of diabetic neuropathy. Further development is on hold on this project.
Insulin-like growth factor-1. Based on the demonstration that insulin-like growth factor-1 can ameliorate experimental diabetic neuropathy, clinical trials have been progressed to phase 2. Development was discontinued during phase 3 in 1997. The reason was that a planned interim evaluation revealed the potential for insulin-like growth factor-1 to exert an angiogenic effect in the eye that could aggravate diabetic retinopathy. Because of the role of insulin-like growth factors during peripheral nervous system development, the insulin-like growth factor signaling system remains a potential therapeutic target for the treatment of peripheral neuropathy and motor neuron diseases in spite of mixed therapeutic results in clinical trials (Sullivan et al 2008).
Recombinant human brain-derived neurotrophic factor. A randomized, double-blind, placebo-controlled study of brain-derived neurotrophic factor showed improvement of detectable cool detection when compared to baseline in the treated group, but not in the placebo group. Further clinical trials were recommended but have not been carried out.
Hepatocyte growth factor. Nonviral gene transfer of human hepatocyte growth factor improves streptozotocin-induced diabetic neuropathy in rats (Kato et al 2005).
Future prospects of treatment of diabetic neuropathy with neurotrophic factors. Advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of neurotrophic factors as treatments for diabetic neuropathy.
Antineoplastic agents-induced neuropathy. Most of the investigations and studies in this area include cisplatin-induced neuropathy as an indication. Preclinical data suggest that several neurotrophic factors, such as nerve growth factor, insulin-like growth factor-1, and neurotrophin-3, merit further investigation in the management of cisplatin-induced neuropathy. Neurotrophin-3 delivery, using direct gene transfer into muscle by in vivo electroporation in a mouse model of cisplatin-induced neuropathy, has shown some beneficial effect, and clinical development has been considered but is not being pursued currently.
The management of antineoplastic agent-induced neuropathy is similar to that of diabetic neuropathy, with the difference that prophylactic therapy is considered along with chemotherapy to prevent the development of peripheral neuropathy. Neurotrophic factors, among other neuroprotective agents, are promising for preventing neurotoxicity resulting from taxanes exposure, but further confirmatory trials are warranted (Argyriou et al 2008). Only nerve growth factor has been studied in clinical trials:
Nerve growth factor. This is the only agent reported to prevent, rather than partially protect, cisplatin-induced neuropathy in an experimental model. The basis for this therapeutic approach is that nerve growth factor impairment has been shown to play a role in the neurotoxicity of oxaliplatin. It was studied in phase 2 clinical trials in patients with peripheral neuropathy due to antineoplastic agents, but no further clinical development has taken place.