title: Continuous delivery of neurotrophin 3 by gene therapy has a neuroprotective effect in experimental models of diabetic and acrylamide neuropathies.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs (LGN), UMR C9923, Centre National de la Recherche Scientifique, Hôpital de la Pitié-Salpétrière, 75651 Paris Cedex 13, France.
authors.forename: P F
authors.initials: PF
authors.lastname: Pradat
authors.forename: P
authors.initials: P
authors.lastname: Kennel
authors.forename: S
authors.initials: S
authors.lastname: Naimi-Sadaoui
authors.forename: F
authors.initials: F
authors.lastname: Finiels
authors.forename: C
authors.initials: C
authors.lastname: Orsini
authors.forename: F
authors.initials: F
authors.lastname: Revah
authors.forename: P
authors.initials: P
authors.lastname: Delaere
authors.forename: J
authors.initials: J
authors.lastname: Mallet
mesh_terms: D000178:Acrylamides / Q000009:adverse effects; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D004594:Electrophysiology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D018696:Neuroprotective Agents; D020933:Neurotrophin 3 / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000008:administration & dosage; D019076:Transgenes
chemical_list: D000178:Acrylamides; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D013311:Streptozocin; D002795:Choline O-Acetyltransferase