Peripheral nerves show spontaneous regenerative responses, but recovery after injury or peripheral neuropathies (toxic, diabetic, or chronic inflammatory demyelinating polyneuropathy syndromes) is slow and often incomplete, and at present no efficient treatment is available. Using well-defined peripheral nerve lesion paradigms, we assessed the therapeutic usefulness of etifoxine, recently identified as a ligand of the translocator protein (18 kDa) (TSPO), to promote axonal regeneration, modulate inflammatory responses, and improve functional recovery. We found by histologic analysis that etifoxine therapy promoted the regeneration of axons in and downstream of the lesion after freeze injury and increased axonal growth into a silicone guide tube by a factor of 2 after nerve transection. Etifoxine also stimulated neurite outgrowth in PC12 cells, and the effect was even stronger than for specific TSPO ligands. Etifoxine treatment caused a marked reduction in the number of macrophages after cryolesion within the nerve stumps, which was rapid in the proximal and delayed in the distal nerve stumps. Functional tests revealed accelerated and improved recovery of locomotion, motor coordination, and sensory functions in response to etifoxine. This work demonstrates that etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, is remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery. Its possible mechanism of action is discussed, with reference to the neurosteroid concept. This molecule, which easily enters nerve tissues and regulates multiple functions in a concerted manner, offers promise for the treatment of peripheral nerve injuries and axonal neuropathies.

Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.

After a traumatic injury of the nervous system or in the course of a neurodegenerative disease, the speed of axonal regeneration and the control of the inflammatory response are fundamental parameters of functional recovery. Spontaneous regeneration takes place in the peripheral nervous system, although the process is slow and often incomplete. There is currently no efficient treatment for enhancing axonal regeneration, including elongation speed and functional reinnervation. Ligands of the translocator protein 18 kDa (TSPO) are currently under investigation as therapeutic means for promoting neuroprotection, accelerating axonal regeneration and modulating inflammation. The mechanisms of action of TSPO ligands involve the regulation of mitochondrial activity and the stimulation of steroid biosynthesis. In the peripheral nervous system, TSPO expression is strongly up‐regulated after injury, primarily in Schwann cells and macrophages, but also in neurones. Its levels return to low control values when nerve regeneration is completed, strongly supporting an important role in regenerative processes. We have demonstrated a role for the benzoxazine etifoxine in promoting axonal regeneration in the lesioned rat sciatic nerve, either after freeze‐injury or complete transection. Etifoxine is already clinically approved for the treatment of anxiety disorders (Stresam^®, Biocodex, Gentilly, France). Daily treatment with etifoxine resulted in a two‐fold acceleration in axonal regeneration, as well as in a marked improvement of both the speed and quality of functional recovery. The neuroregenerative effects of etifoxine are likely to be mediated by TSPO, and they may involve an increased synthesis of pregnenolone and its metabolites, such as progesterone. After freeze‐injury of the sciatic nerve, administration of etifoxine also strongly reduced the number of activated macrophages and decreased the production of the inflammatory cytokines tumour necrosis factor‐α and interleukin‐1β. Thus, this drug offers promise for the treatment of peripheral nerve injuries and axonal neuropathies. It may also be used as a lead compound in the development of new TSPO‐based neuroprotective approaches.

STEM CELLS Translational Medicine works to advance the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best practices and ultimately improve patient outcomes.

Spinal cord injuries often result in irreversible loss of motor and somatosensory functions below the lesion level. Treatment is limited to physiotherapy aimed at compensating disability. We previously showed that re-establishment of tissue continuity can be achieved in animal models through nerve autografts implanted between the rostral spinal ventral horn and the caudal ventral roots. Rostral motor neuron axons could thus reach peripheral targets, leading to some return of motor function. We used a similar approach in a paraplegic patient with stabilized clinical states three years after spinal cord traumatic damage at the T9 level. Three segments from autologous sural nerves were implanted into the right and left antero-lateral quadrant of the cord at T7-8 levels, then connected to homolateral L2-4 lumbar ventral roots, respectively. Eight months after surgery, voluntary contractions of bilateral adductors and of the left quadriceps were observed. Muscular activity was confirmed by motor unit potentials in response to attempted muscle contraction. Motor-evoked potentials from these muscles were recorded by transcranial magnetic stimulation. These data support the hypothesis that muscles have been re-connected to supra-spinal centers through motor neurons located in the rostral stump of the damaged cord. They suggest that delayed surgical reconstruction of motor pathways may contribute to partial functional recovery.