BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury

Abstract

Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies.

Atomic Force Microscopy as a Tool to Assess the Specificity of Targeted Nanoparticles in Biological Models of High Complexity

“…TMC with an average number molecular weight () of 43.3 kDa, a degree of acetylation of 15.7% and a quaternization degree of 30.1% was used . To attain nanoparticle neurotropism, our group has been exploring the tethering of a pegylated HC fragment at the NPs surface . Consequently, thiol groups were introduced into the TMC polymer backbone (TMC SH ) by a previously described method .…”

“…To attain nanoparticle neurotropism, our group has been exploring the tethering of a pegylated HC fragment at the NPs surface . Consequently, thiol groups were introduced into the TMC polymer backbone (TMC SH ) by a previously described method . During TMC SH complexation with plasmid DNA, the presence of thiol pending groups further contributes to the crosslinking of the polycation, stabilizing the resulting complexes, and allows the subsequent functionalization of the NPs.…”

“…In this work, we aimed at testing the specificity of gene carrying trimethyl chitosan (TMC) NPs actively targeted toward neuronal populations in complex biological models, that include in vitro heterogeneous primary neural cell cultures and innervated histological tissue sections, by MRFS. To promote the NP selective targeting toward neuronal cells, TMC NPs functionalized with the non‐toxic and neurotropic carboxylic C‐terminal fragment of the tetanus toxin heavy chain (HC), with proven efficacy both in vitro and in vivo, were used.…”

BDNF‐TrkB pathway mediates antidepressant‐like roles of H2S in diabetic rats via promoting hippocampal autophagy

“…Brain‐derived neurotrophic factor (BDNF) is a neurotrophic factor and exists widely in the central nervous system (CNS), such as the hippocampus and cortex . BDNF plays crucial roles in survival, development, differentiation, and proliferation of brain neurons and repairs of injured nerve cells, which is mediated by the high‐affinity tropomysin‐related kinase B (TrkB) receptor . It has been reported that serum BDNF level is significantly low in depressed and diabetic patients and negatively correlated with the risk of depression .…”

“…development, differentiation, and proliferation of brain neurons and repairs of injured nerve cells, 7,8 which is mediated by the high-affinity tropomysin-related kinase B (TrkB) receptor. 9 It has been reported that serum BDNF level is significantly low in depressed and diabetic patients and negatively correlated with the risk of depression.…”