Gene therapy and peripheral nerve repair: a perspective

Abstract

Clinical phase I/II studies have demonstrated the safety of gene therapy for a variety of central nervous system disorders, including Canavan's, Parkinson's (PD) and Alzheimer's disease (AD), retinal diseases and pain. The majority of gene therapy studies in the CNS have used adeno-associated viral vectors (AAV) and the first AAV-based therapeutic, a vector encoding lipoprotein lipase, is now marketed in Europe under the name Glybera. These remarkable advances may become relevant to translational research on gene therapy to promote peripheral nervous system (PNS) repair. This short review first summarizes the results of gene therapy in animal models for peripheral nerve repair. Secondly, we identify key areas of future research in the domain of PNS-gene therapy. Finally, a perspective is provided on the path to clinical translation of PNS-gene therapy for traumatic nerve injuries. In the latter section we discuss the route and mode of delivery of the vector to human patients, the efficacy and safety of the vector, and the choice of the patient population for a first possible proof-of-concept clinical study.

Keywords: Schwann cell; adeno-associated viral vector; gene therapy; lentiviral vector; neurosurgery.

Figure 1

Anatomical relationships in the peripheral nervous system (PNS) and sites of viral vector-mediated gene delivery. The PNS consists of primary sensory neurons (blue and green: nociceptive and proprioceptive neurons) in the dorsal root ganglia (DRG) and motor neurons (red) in the ventral horn of the spinal cord. The axons form a mixed nerve that innervates the skin and muscle. Successful gene delivery to primary sensory and motor neurons and to Schwann cells, the resident glia cells of peripheral nerves, has been reported with various viral vectors. To target primary sensory and motor neurons two routes of delivery have been used successfully: direct intraganglionic or intraspinal injection and intrathecal (IT) delivery. Injection of a viral vector in the nerve stump distal to the lesion or in a nerve graft that bridges the lesion results in transduction of Schwann cells.

Figure 2

AAV2-mediated transduction of a human sural nerve segment. Surplus human nerve material was obtained from the operation room and anonymized as stated in the code of conduct for responsible use of human tissue and medical research (Federa, 2011). Nine AAV serotypes were compared for their transduction efficiency by injecting 1.85 × 10¹⁰ gc/cm nerve and culturing the nerve segments for 14 days. After 14 days nerve segments were immersion fixed with paraformaldehyde and 20 μm sections were prepared. The upper panel show a section through a human sural nerve stained for GFP. The middle panel shows the same image stained for the nuclear stain Hoechst and the lower panel shows the merged images of the two panels. AAV2 transduced numerous cells that display the typical longitudinal shape of Schwann cells and this serotype was superior to all other serotypes tested. More details on this study can be found in Hoyng et al. (2015).