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Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis 总被引:1,自引:1,他引:0
Nizzardo M Simone C Falcone M Riboldi G Rizzo F Magri F Bresolin N Comi GP Corti S 《Cellular and molecular life sciences : CMLS》2012,69(10):1641-1650
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle
weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues
to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal
muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved
with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches
for ALS, considering what has been done and the possible future directions for effective application of the latest generation
of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific
ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of
neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical
progress in treating ALS. 相似文献
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Irene Faravelli Giulietta Riboldi Monica Nizzardo Chiara Simone Chiara Zanetta Nereo Bresolin Giacomo P. Comi Stefania Corti 《Cellular and molecular life sciences : CMLS》2014,71(17):3257-3268
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3–5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application. 相似文献
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Federica Rizzo Giulietta Riboldi Sabrina Salani Monica Nizzardo Chiara Simone Stefania Corti Eva Hedlund 《Cellular and molecular life sciences : CMLS》2014,71(6):999-1015
Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients. 相似文献
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Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells 总被引:3,自引:3,他引:0
M. Nizzardo C. Simone M. Falcone F. Locatelli G. Riboldi G. P. Comi S. Corti 《Cellular and molecular life sciences : CMLS》2010,67(22):3837-3847
Motor neuron diseases (MNDs) are a group of neurological disorders that selectively affect motor neurons. There are currently
no cures or efficacious treatments for these diseases. In recent years, significant developments in stem cell research have
been applied to MNDs, particularly regarding neuroprotection and cell replacement. However, a consistent source of motor neurons
for cell replacement is required. Human embryonic stem cells (hESCs) could provide an inexhaustible supply of differentiated
cell types, including motor neurons that could be used for MND therapies. Recently, it has been demonstrated that induced
pluripotent stem (iPS) cells may serve as an alternative source of motor neurons, since they share ES characteristics, self-renewal,
and the potential to differentiate into any somatic cell type. In this review, we discuss several reproducible methods by
which hESCs or iPS cells are efficiently isolated and differentiated into functional motor neurons, and possible clinical
applications. 相似文献
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