597. AAV. NT-3 Treatment Attenuates Spontaneous Autoimmune Peripheral Polyneuropathy

Abstract

The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout non-obese diabetic (NOD) mice demonstrates overlapping clinical features with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Secondary axonal loss is prominent in the progressive phase of this neuropathy. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell (SC) survival and differentiation and stimulates neurite outgrowth and myelination. Recently, NT-3 delivered in bone marrow-derived neural stem cells was shown to exert therapeutic effect, by reducing the inflammation and accelerating remyelination in experimental encephalomyelitis (EAE), an animal model of multiple sclerosis. These findings led to considerations of AAV.NT-3 gene therapy via intramuscular delivery into SAPP mice to attenuate the disease. The results show AAV.NT-3 injection into gastrocnemius muscle of 25 week old SAPP mice produced measurable NT-3 levels in the serum at 7 weeks post gene delivery, sufficient to protect sciatic nerve motor function and compound muscle action potentials (CMAPs). Sciatic nerves of mice, receiving gene transfer had a significantly greater number of remyelinated fibers and decreased infiltration of CD3+ T cells compared to controls. These data correlated with reduced expression of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor (Tnf-α) and increased expression of anti-inflammatory markers, interleukin-10 and forkhead box-P3 (Foxp3) in the sciatic nerve. The treatment also increased the percentage of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the spleen. This proof-of-principle study established a therapeutic benefit by neuroprotective and immunomodulatory effects of AAV-NT-3 treatment in SAPP. This study demonstrates the potential clinical translational path for AAV delivered NT-3 for refractory cases of CIDP..