Stem cells and neurodegenerative diseases (5)
Amyotrophic lateral sclerosis
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This fatal neurodegenerative disease is caused by degeneration of the motor neurons of the spinal cord, brain stem and primary motor cortex, which leads to thinning of muscle tissue, paralysis and, eventually, death due to respiratory failure. First described by Charcot in 1874, this disease is also known as Lou Gehrig's disease. Amyotrophic lateral sclerosis is associated with frontotemporal lobe dementia due to symptomatic, clinical, genetic and pathological similarities. With the simultaneous development of amyotrophic lateral sclerosis and frontal-parietal lobe dementia, the patient's life expectancy is further shortened.
These two diseases are often considered as two extreme manifestations of the same spectrum of diseases. Ling et al. We have obtained genetic evidence of this by demonstrating that patients with amyotrophic lateral sclerosis and a combination of two diseases are carriers of the same mutations. Many mutations lead to the development of familial amyotrophic lateral sclerosis. These include mutations of the genes PFN1, FUS/TLS (fusion in sarcoma/translocation in liposarcoma), TARDBP or TDP-43 (TAR-DNA-binding protein-43), UBQLN2, C9ORF72, SOD1 (superoxide dismutase-1), HNRNPA1, OPTN and VCP. Recently, a new TBK1 gene has been discovered, which plays a critical role in inflammation and autophagy, initially associated with the pathogenesis of amyotrophic lateral sclerosis.
The pathogenesis of the sporadic form of the disease is associated with glutamate excitotoxicity, mitochondrial dysfunction, protein aggregation, oxidative stress, lack of neurotropic factors, glial cell dysfunction and axonal transport disorders. All this eventually leads to the accumulation of intracellular neurofilaments. The only commercially available drug that helps alleviate the symptoms of the disease is riluzole, but it loses its effectiveness after 6 months.
Amyotrophic lateral sclerosis has been actively studied in animal models, but several unsuccessful clinical studies have demonstrated the limitations of in vivo research. Banks of patient-specific iPSCs bring us closer to personalized medicine and are a good alternative for screening the effectiveness of potential drugs and compounds for the treatment of amyotrophic lateral sclerosis.
Transplantation therapy using stem cells can be effectively used as a therapeutic approach to the treatment of this serious disease. Mesenchymal and hematopoietic stem cells were effectively used for transplantation into the damaged spinal cord and had a positive effect on the course of amyotrophic lateral sclerosis. However, studies have been conducted on small groups of patients, and scrupulous research work is currently underway to make this approach applicable to larger groups of patients. Neural stem cells, embryonic stem cells, glial progenitor cells and induced pluripotent stem cells are also potential alternatives for use in transplantation. There is a hypothesis that when donor cells are transplanted in close proximity to damaged motor neurons, they not only have an immunomodulatory effect, but also secrete trophic factors that improve the overall therapeutic potential of the transplant. Such transplants can effectively delay the progress and even the initiation of the disease.
Direct or peripheral injections of mesenchymal stem cells into the spinal cord of patients are a powerful therapeutic approach to the treatment of amyotrophic lateral sclerosis, and several studies have described the therapeutic potential of these cells. A number of studies describe the positive aspects of transplanted mesenchymal stem cells used to deliver the required neurotrophic factors that help prevent the death of motor neurons, improve the survival of experimental animals and slow down the progress of the disease.
Genetically modified mesenchymal stem cells secreting glial neurotropic factor contribute to an increase in the lifespan of a rat model of amyotrophic lateral sclerosis by preventing the death of motor neurons. Developed by BrainStorm Cell Therapeutics, the "NurOwn" product is specialized mesenchymal stem cells capable of secreting neurotropic factors and differentiating into nerve cells. Currently, "NurOwn" is at the stage of clinical trials. In addition, to date, many clinical studies have already been conducted on the efficacy and safety of mesenchymal stem cells, and quite a large number of such studies have not yet been completed.
Nerve stem cells, capable of differentiating only into cells of the central nervous system, are widely used in the therapy of neurodegenerative diseases. When administered to animal models of amyotrophic lateral sclerosis, these cells had a protective effect on the motor neurons surrounding them. Stem cells not only provide symptomatic relief, but also contribute to the restoration of brain tissue through the elimination of damage and neurogenesis triggered in the damaged area of the spinal cord. There is a publication describing the successful transplantation of nerve stem cells from aborted embryos into the spinal cord of a patient. The results of a phase 1 clinical trial have also been documented, indicating sufficient safety of stem cell therapy and the feasibility of its use for the treatment of large groups of patients.
Familial cases of amyotrophic lateral sclerosis can be modeled on embryonic stem cells with disease-causing mutations, whereas sporadic cases require the use of patient-specific iPSCs. The use of iPSC described in the literature for modeling amyotrophic lateral sclerosis indicates the possibility of using motor neurons obtained from the patient's iPSC to reproduce the phenotypes of the disease. Amyotrophic lateral sclerosis causes complex physiological manifestations, and there are not enough cells of one type to model it. It has been demonstrated that astrocytes expressing superoxide dismutase-1 derived from embryonic stem cells have a toxic effect on the motor neurons surrounding them, whereas iPSC-bearing astrocytes carrying the TDP-43 mutation do not exhibit toxicity. This indicates the feasibility of using a joint culture of different cell types to simulate a complex disease. One of the disadvantages of modeling amyotrophic lateral sclerosis in vitro is the short survival of motor neurons in culture, which limits the possibilities of studying phenotypic signs manifested in aging diseased tissues. However, transplantation of motor neurons obtained from iPSCs of an animal model increases their survival rate. Transplanted cells can later be isolated from postmortem rodent tissue samples to visualize disease phenotypes, which is a possible solution to the problem.
Studies have shown that a population of nerve progenitor cells enriched with glial cells obtained from iPSCs can be successfully transplanted into the spinal cord of mice with amyotrophic lateral syndrome. These transplanted cells demonstrate good survival, differentiation potential, and also increase the life expectancy of animals. Stem cell therapy has been the subject of discussion for a long time. The positive aspects of its use cannot be underestimated, however, large-scale clinical studies aimed at developing an effective method of therapy and possible cure have not yet been completed.
Continued: Huntington's disease
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02.03.2017