Martijn R Tannemaat1, Joost Verhaagen, Martijn Malessy. 1. Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.
Abstract
OBJECTIVE: Despite great advancements in surgical repair techniques, a considerable degree of functional impairment remains in the majority of patients after peripheral nerve reconstruction. New concepts to promote regeneration of the peripheral nerve are needed since it is generally held that surgery has reached an optimal technical refinement. Several neurotrophic factors stimulate regeneration of the peripheral nerve, but the effects of the exogenous application of these factors have so far been limited, possibly as the result of their fast degradation and unwanted side effects after systemic application. These problems can be resolved with the recent development of non-toxic, non-immunogenic viral vectors that drive local, long-term transgene expression. METHODS: The literature was searched for papers describing the application of gene therapy, specifically viral vectors, in peripheral nerve lesion models. RESULTS: Retroviral vectors have been used successfully for the ex vivo transduction of Schwann cells, before seeding in artificial nerve guides. Lentiviral (LV) vectors direct long-term transgene expression in Schwann cells in rat peripheral nerves. LV vectors are also capable of transducing cultured segments of human sural nerve, thereby providing 'proof of concept' for the feasibility of genetic modification of sural nerve transplants in a clinical setting. DISCUSSION: In the near future, viral vectors will increasingly be used to study a wide range of neurotrophic factors and other potentially therapeutic proteins for their effect on peripheral nerve regeneration in animal models. If this approach leads to beneficial effects on regeneration and functional recovery, the safety and clinical applicability of these viral vectors will allow the rapid translation of basic research to clinical trials. This makes the use of viral vectors a highly attractive concept that holds great promise as a novel adjuvant therapy to peripheral nerve reconstruction.
OBJECTIVE: Despite great advancements in surgical repair techniques, a considerable degree of functional impairment remains in the majority of patients after peripheral nerve reconstruction. New concepts to promote regeneration of the peripheral nerve are needed since it is generally held that surgery has reached an optimal technical refinement. Several neurotrophic factors stimulate regeneration of the peripheral nerve, but the effects of the exogenous application of these factors have so far been limited, possibly as the result of their fast degradation and unwanted side effects after systemic application. These problems can be resolved with the recent development of non-toxic, non-immunogenic viral vectors that drive local, long-term transgene expression. METHODS: The literature was searched for papers describing the application of gene therapy, specifically viral vectors, in peripheral nerve lesion models. RESULTS: Retroviral vectors have been used successfully for the ex vivo transduction of Schwann cells, before seeding in artificial nerve guides. Lentiviral (LV) vectors direct long-term transgene expression in Schwann cells in rat peripheral nerves. LV vectors are also capable of transducing cultured segments of human sural nerve, thereby providing 'proof of concept' for the feasibility of genetic modification of sural nerve transplants in a clinical setting. DISCUSSION: In the near future, viral vectors will increasingly be used to study a wide range of neurotrophic factors and other potentially therapeutic proteins for their effect on peripheral nerve regeneration in animal models. If this approach leads to beneficial effects on regeneration and functional recovery, the safety and clinical applicability of these viral vectors will allow the rapid translation of basic research to clinical trials. This makes the use of viral vectors a highly attractive concept that holds great promise as a novel adjuvant therapy to peripheral nerve reconstruction.