Neurotrophic factors (NFs) are promising agents for the treatment of peripheral neuropathies such as diabetic neuropathy. However, the value of treatment with recombinant NF is limited by the short half-lives of these molecules, which reduces efficiency, and by their potential toxicity. We explored the use of intramuscular injection of a recombinant adenovirus encoding NT-3 (AdNT-3) to deliver sustained low doses of NT-3. We assessed its effect in two rat models: streptozotocin (STZ)-induced diabetes, a model of early diabetic neuropathy characterized by demyelination, and acrylamide experimental neuropathy, a model of diffuse axonal neuropathy which, like late-onset human diabetic neuropathy, results in a diffuse sensorimotor neuropathy with dysautonomy. Treatment of STZ-diabetic rats with AdNT-3 partially prevented the slowing of motor and sensory nerve conduction velocities (p < 0.01 and p < 0.0001, respectively). Treatment with AdNT-3 of acrylamide-intoxicated rats prevented the slowing of motor and nerve conduction velocities (p < 0.001 and p < 0.0001, respectively) and the decrease in amplitude of compound muscle potentials (p < 0.0001), an index of denervation. Acrylamide-intoxicated rats treated with NT-3 had higher than control levels of muscle choline acetyltransferase activity (p < 0.05), suggesting greater muscle innervation. In addition, treatment of acrylamide-intoxicated rats with AdNT-3 significantly improved behavioral test results. Treatment with AdNT-3 was well tolerated with minimal muscle inflammation and no detectable general side effects. Therefore, our results suggest that NT-3 delivery by adenovirus-based gene therapy is a promising strategy for the prevention of both early diabetic neuropathy and axonal neuropathies, especially late axonal diabetic neuropathy.

Sensory neuropathies are a frequent and dose-limiting complication resulting from treatment with cisplatin. cisplatin; neuropathy Cisplatin is an efficient antineoplastic agent. However, its use is limited by its toxicity. The associated vomiting and nephrotoxicity are currently reduced by the use of antiemetics and vigorous hydration. The most problematic complication of cisplatin treatment is its neurotoxicity in the peripheral nervous system. Cisplatin causes a dosedependent and dose-limiting sensory neuropathy, which is often disabling and from which recovery is often slow and incomplete. 1 Neurotrophin-3 (NT-3) is a promising agent for the prevention and treatment of cisplatininduced neuropathy. Indeed, NT-3 promotes the survival of the large fiber sensory neurones 2 affected in cases of cisplatin-induced neuropathy. 1 Circulating NT-3 can readily reach dorsal root ganglia (DRG), which are the main target of cisplatin toxicity, 3 as there is no bloodnerve barrier. 4 Neurotrophic factors can therefore easily access the large sensory neurones of DRG. Recombinant NT-3 can prevent experimental sensory neuropathies in rats. 5,6 However, the clinical use of recombinant neurotrophic factors is limited by their poor bioavailability after systemic administration: the plasma half-life for NT-3 is only 1.28 min after intravenous administration in the rat. 7 We recently developed a non-viral gene transfer strategy to deliver continuous low doses of NT-3 into the