10 research outputs found
Gene therapy strategies in neurodegenerative diseases
Treatment of neurodegenerative diseases by
classical pharmacotherapy is restricted by blood-brain
barrier which prevents access to the brain of potentially
therapeutic molecules. Recent progress in the knowledge
of pathophysiological molecular processes, and in the
development of molecular biotechnology have opened
the way to new therapeutic interventions for these
disorders. This chapter reviews the most recent gene
therapy strategies using experimental models for
neurodegenerative diseases
Neural stem cells and the quest for restorative neurology
A great deal of interest has attracted the
attention of researchers on the potential use of (neural)
stem cells in cell replacement or restorative therapies for
heretofore incurable CNS pathologies such as brain
stroke, spinal cord injury, Parkinson’s disease or
multiple sclerosis. This short perspective illustrates our
view of neural stem cell research with a focus on the
stem cell concept, on the in situ identity of neural stem
cells and on selected aspects of embryonic and adult
neurogenesis. A brief survey of current stem cell-based
experimental literature tries to provide a realistic picture
of how far we have gone in the quest to establish a
restorative neurology
Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes
The lack of axonal regeneration in the injured adult mammalian spinal cord leads to permanent functional disabilities. The inability of neurons to regenerate their axon is appreciably due to an inhospitable environment made of an astrocytic scar. We generated mice knock-out for glial fibrillary acidic protein and vimentin, the major proteins of the astrocyte cytoskeleton, which are upregulated in reactive astrocytes. These animals, after a hemisection of the spinal cord, presented reduced astroglial reactivity associated with increased plastic sprouting of supraspinal axons, including the reconstruction of circuits leading to functional restoration. Therefore, improved anatomical and functional recovery in the absence of both proteins highlights the pivotal role of reactive astrocytes in axonal regenerative failure in adult CNS and could lead to new therapies of spinal cord lesions.This work was supported by Institut National de la Sante et de la Recherche Medicale, Institut pour la Recherche sur la Moelle Epiniere, and Verticale.Peer reviewe
Potential adverse effects of cyclosporin A on kidneys after spinal cord injury
Study design:Cell transplantation strategies are gaining increasing interest for spinal cord injury (SCI) with the objective of promoting spinal cord repair. To avoid allogenic graft rejection, an adequate immune suppression is required, and one of the most potent and commonly used immunosuppressives is cyclosporin A (CsA). In SCI, permanent sensory motor loss is combined with modifications of drug absorption, distribution and elimination.Objectives:The objectives of this study were to thoroughly explore histological and functional outcomes of CsA treatment in a rat model of spinal cord compression.Setting: Experiments were carried out at the Institute for Neurosciences of Montpellier (France), the Integrative Biology of Neurodegeneration Laboratory (Spain) and in the Novartis Institutes for BioMedical Research (Switzerland) for CsA blood concentration determination.Methods:We first evaluated histological outcomes of CsA treatment on kidneys and spinal cord after SCI. We then investigated whether SCI modified CsA blood concentration. Finally, using behavioral analysis, we assessed the potential CsA impact on functional recovery.Results:When spinal-cord-injured rats were treated with a CsA dose of 10 mg kg -1 per day, we observed deleterious effects on kidneys, associated with modifications of CsA blood concentration. Adding an antibiotic treatment reduced kidney alteration without modifying CsA blood concentration. Finally, we showed that CsA treatment per se modified neither functional recovery nor lesion extension.Conclusion:This study pinpoints the absolute requirement of careful CsA monitoring in the clinical setting for patients with SCI to minimize potential unexpected effects and avoid therapeutic failure.Peer reviewe
Integration of genetically modified adult astrocytes into the lesioned rat spinal cord
Combination of ex vivo gene transfer and cell transplantation is now considered as a potentially useful strategy for the treatment of spinal cord injury. In a perspective of clinical application, autologous transplantation could be an option of choice. We analyzed the fate of adult rat cortical astrocytes genetically engineered with a lentiviral vector transplanted into a lesioned rat spinal cord. Cultures of adult rat cortical astrocytes were infected with an HIV-1-derived vector (TRIP-CMV-GFP) and labeled with the fluorescent dye Hoechst. Transfected and labeled astrocyte suspension was injected at T11 in rats in which spinal cord transection at T7-T8 levels had been carried out 1 week earlier. Six weeks after grafting, the animals were sacrificed and transplants were retrieved either by Hoechst fluorescence or by immunohistochemistry for detection of glial fibrillary acidic protein (GFAP) and vimentin. Grafted astrocytes expressing green fluorescent protein (GFP) were found both at the injection and transection sites. Genetically modified astrocytes thus survived, integrated, and migrated within the host parenchyma when grafted into the completely transected rat spinal cord. In addition, they retained some ability to express the GFP transgene for at least 6 weeks after transplantation. Adult astrocytes infected with lentiviral vectors can therefore be a valuable tool for the delivery of therapeutic factors into the lesioned spinal cord.Contract grant sponsor: Institut de Recherche sur la Moelle Epiniere;Contract grant sponsor: Association Francaise des Myopathies.Peer reviewe
Could enhanced reflex function contribute to improving locomotion after spinal cord repair?
Although numerous treatments have been found to improve locomotion in spinal cord injured mammals, the underlying mechanisms are very poorly understood. Some of the main possibilities are: (1) regeneration of axons across the injury site and the re-establishment of descending pathways needed to voluntarily initiate and maintain stepping in the hind legs, (2) enhanced effectiveness of undamaged neurons in preparations with incomplete transections of the cord, (3) non-specific facilitation of reflexes and intrinsic spinal networks by transmitters released from regenerated axons and/or by substances introduced by the treatment, and (4) enhanced trunk movements close to the injury site strengthening the mechanical coupling of the trunk to the hind legs via spinal reflexes. In addition, any procedure that even slightly improves stepping may be further enhanced by use-dependent modification of reflex pathways and interneuronal networks in the lumbar cord. The emphasis of this review is on the contribution of spinal reflexes to the patterning of motor activity for walking, and how enhancing reflex function may contribute to the improvement of locomotion by treatments aimed at restoring locomotion after complete transection of the spinal cord