Gene Therapy in Peripheral Nerve Reconstruction Approaches

Abstract

Gene transfer to a transected peripheral nerve or avulsed nerve root is discussed to be helpful where neurosurgical peripheral nerve reconstruction alone will not result in full recovery of function. Axonal regeneration is supposed to be facilitated by this new therapeutic approach via delivery of specific regeneration promoting molecules as well as survival proteins for the injured sensory and motor neurons. Therefore gene therapy aims in long-term and site-specific delivery of those neurotrophic factors. This paper reviews methods and perspectives for gene therapy to promote functional recovery of severely injured and thereafter reconstructed peripheral nerves. Experimental in vivo and ex vivo gene therapy approaches are reported by different groups. In vivo gene therapy generally uses direct injection of cDNA vectors to injured peripheral nerves. Ex vivo gene therapy is based on the isolation of autologous cells followed by genetic modification of these cells in vitro and re-transplantation of the modified cells to the patient as part of tissue engineered nerve transplants. Vectors of different origin are published to be suitable for peripheral nerve gene therapy and this review discusses the different strategies with regard to their efficiency in gene transfer, their risks and their potential relevance for clinical application.

Semi‐Synthetic Ecdysteroids as Gene‐Switch Actuators: Synthesis, Structure–Activity Relationships, and Prospective ADME Properties

“…Owing to the ability to control protein expression levels, the incorporation of gene switches into gene therapeutic regimens may render those therapies currently under development more effective, and also enable wider extension among indications in cancer, [7] cardiovascular diseases, [8,9] diabetes, neurodegenerative disorders, [10,11] motor neuron diseases, muscular dystrophy, [12] cystic fibrosis, [13,14] neuropathic pain, [15] rheumatoid arthritis [16,17] and regenerative medicine in general. [18,19] Additionally, gene switches have biopharmaceutical applications in areas such as cell-based assays and animal models for developmental drug testing, as well as biotherapeutics and biomaterials production. [20] Among the various available gene-switch platforms, the insect ecdysteroidregulated switches are refractory to human endogenous steroids, and typically show very low basal transgene expression, high inducibility, and broad dose-response gradation-usually outperforming other systems in each of these aspects.…”

Nanotechnology versus stem cell engineering: in vitro comparison of neurite inductive potentials

“…The genetically engineered BMSCs could potentially be transplanted within tissue-engineered nerve conduits, as has been successfully done before with genetically engineered Schwann cells. 4 In order to compare the feasibility of optimized NTF delivery increasing the neurite outgrowth in vitro, we utilized adult DRG explant organotypic cultures as well as neonatal DRG drop cultures. The DRG neurite outgrowth model is widely used to assess the neurite outgrowth in a specific environment.…”

“…cultures were maintained for 1 day. (C) a density of 30×10 4 egFP-Pc-12 cells was mixed with either np-NTFs or 40×10 4 nT-BMscs or FgF-2 18kDa -BMscs in a volume of 1 ml 0.5% NVr-gel (containing Pc-12 cell differentiation medium) and transferred into a 24-multiwell culture well. cultures were maintained for 5 days.…”

“…The main drawback in NTF application is the short half-life time, causing minimal efficacy of single NTF application at the time of reconstructive surgery or systemic application. Different ways to ensure extended availability of added NTFs at the site 2,3 stefano geuna 1 of nerve reconstruction have been attempted in recent years, including gene therapy via transplanted Schwann cells 4 or nanotechnology approaches. 5 Ex vivo gene therapy can be used to genetically induce the overexpression of selected NTFs in cells that are later transplanted as part of tissue-engineered nerve grafts.…”

Perspectives in regeneration and tissue engineering of peripheral nerves

“…One of the most promising strategies for local growth factor delivery is probably gene trans-fer and this approach is also getting more and more interest in the repair of the peripheral nervous system (Haastert and Grothe, 2007;Tannemaat et al, 2009;Zacchigna and Giacca, 2009;Pereira Lopes et al, in press). Various studies in animal models have shown that peripheral nerve regeneration can be improved by gene trans-fer.…”