In vitro experiments and work with knock-out mice have shown the physiological importance of neurotrophic factors (NF) to the development and survival of neurons of the peripheral nervous system. Thus NF may be useful in the treatment of peripheral neuropathies (PN). PN may be more amenable than CNS diseases to the systemic delivery of NF due to the absence of the blood-brain barrier.

The objectives of NF treatment are: 1/ to compensate for a putative deficiency of NF associated with the pathogenesis of PNs such as diabetic neuropathy; 2/ to stop or slow disease progression by acting on the biochemical pathways involved in the neuro-degenerative cascade; and 3/ to enhance axonal sprouting.

The efficacy of NF treatment has been demonstrated in animal models that mimic various neuropathies e.g. , those related to diabetes or to chemotherapeutic agents. However, a phase 3 trial in diabetic neuropathy and a phase 2 trial in HIV-related neuropathy have failed to demonstrate any beneficial effects of NF therapy in these conditions.

This paper discusses the factors that may account for such disappointing results. A major limitation of the systemic route of administration is the poor bioavailability of NFs due to their short half-life. Alternative modes of delivery may be more appropriate, in particular muscle-based gene therapy which would allow the continuous delivery of sustained levels of NF into the circulation. This route has been used effectively in animal models of motor and sensory PNs. A recent clinical trial with muscle-based gene therapy for the deliver of VEGF in chronic ischaemic neuropathy has shown the efficacy and safety of this approach. Another promising treatment is the use of small molecules that induce the endogenous synthesis of NF such as xaliprodene and 4-methylcathecol.

131 references.