The application of viral vectors to enhance regeneration after peripheral nerve repair Martijn R. Tannemaat* { , Joost Verhaagen* and Martijn Malessy { *Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands { Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands 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. [Neurol Res 2008; 30: 1039–1046] Keywords: Peripheral nerve; nerve repair; nerve regeneration; viral vectors INTRODUCTION: PERIPHERAL NERVE REPAIR The first series of successful surgical reconstructions of the peripheral nerve were described shortly after the Second World War 48 . Since then, a better under- standing of peripheral nerve anatomy, the evolution of surgical techniques, including epineurial suturing and the introduction of the operating microscope, have led to a significant improvement in the clinical outcome of surgery. Surgery is currently the preferred treatment for the transected nerve and consists of direct, tension-free, suture coaptation of nerve stumps. A detrimental factor to nerve regeneration is the occurrence of fibrosis in the gap, which may lead to neuroma formation, thereby greatly reducing the chance of successful axonal regeneration. In such instances, the neuroma is resected and autologous nerve grafts are used as scaffolds to bridge the gap between the proximal and distal nerve stumps 48 . Functional recovery after peripheral nerve reconstruc- tion is almost never complete, and a considerable degree of functional impairment usually remains. The clinical outcome of repair is especially limited in adults, in proximal nerve lesions such as brachial plexus lesions and when long nerve transplants have to be used 48 . It is generally held that microsurgery has now reached an optimal technical refinement and new concepts have to be developed to further promote recovery of function after peripheral nerve repair 35 . A new conceptual framework is currently emerging from a better under- standing of the molecular basis of nerve regeneration and the application of novel intervention strategies, including viral vector mediated gene transfer. In this review, we first describe several neurotrophic factors that play a role in regeneration of the peripheral nerve and how these have been applied exogenously to enhance the results of nerve repair. Subsequently, we discuss the currently available non-viral and viral vectors for gene transfer and summarize their use in Correspondence and reprint requests to: Martijn Malessy, Neurosurgeon Neurosurgery, Leiden University Medical Center, Albinusdreef 2, Leiden 2300, The Netherlands. [malessy@lumc.nl] Accepted for publication August 2008. # 2008 W. S. Maney & Son Ltd Neurological Research, 2008, Volume 30, December 1039 10.1179/174313208X362514