Stem Cell Treatment for ALS

ALS Stem Cell Treatment

ALS Stem Cell Treatment

"My life and millions of others are in the hands of Congress. We are already seeing the incredible potential of stem cells to replace what is destroyed in ALS, but we need the federal government to mentor research along in the most responsible, humane way.” Pointing out that, “non-profits like Project A.L.S. and private industry have started stem cell replacement on the right track,”...“do the right thing and take us to the next level with this life-saving science.

Jenifer Estess (1963–2003) founder of Project A.L.S testifying in 2000 before Senator Arlen Specter’s sub-committee on Labor, Health, Human Services and Education

Organizatiom of the Brain: Cell Types

Stem Cell Treatment for ALS

 

ALS Stem Cell Treatment Case Review

Amyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig's disease, is a form of motor neuron disease  caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input.

The condition is often called Lou Gehrig's disease in North America, after the New York Yankees baseball player who was diagnosed with the disease in 1939. The disorder is characterized by rapidly progressive weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia, and respiratory compromise. Sensory function generally is spared, as is autonomic, and oculomotor activity. ALS is a progressive, fatal, neurodegenerative disease

Signs and symptoms

The disorder causes muscle weakness and atrophy throughout the body caused by degeneration of the upper and lower motor neurons. Unable to function, the muscles weaken and atrophy. Affected individuals may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually, but not always, spared.

Cognitive function is generally spared for most patients although some (~5%) also have frontotemporal dementia. A higher proportion of patients (~30-50%) also have more subtle cognitive changes which may go unnoticed but are revealed by detailed neuropsychological testing. Sensory nerves and the autonomic nervous system, which controls functions like sweating, are generally unaffected but may be involved for some patients.

Initial symptoms

The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include muscle fasciculation (twitching), cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first. About 75% of people contracting the disease experience "limb onset" ALS.

SOD1

The cause of ALS is not known, though an important step toward determining the cause came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn superoxide dismutase (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism again largely by the mitochondria. Free radicals can accumulate and cause damage to both mitochondrial and nuclear DNA and proteins within cells.

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Riluzole is currently the only FDA approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.

Diagnosis

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.

ALS Stem Cell Treatment and stem cell therapy. AlS treatment studies and stem cell protocols:
Related Articles Stem cells in amyotrophic lateral sclerosis: Ready for prime time? Neurology. 2016 07 26;87(4):348-9 Authors: Appel SH, Armon C PMID: 27358334 [PubMed - indexed for MEDLINE]
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Related Articles [Advances in the Development of Treatments for Amyotrophic Lateral Sclerosis]. Nihon Naika Gakkai Zasshi. 2016 Oct;105(10):2055-62 Authors: Aoki M PMID: 30178967 [PubMed - indexed for MEDLINE]
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Related Articles Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat Commun. 2016 10 31;7:13283 Authors: Tian F, Yang W, Mordes DA, Wang JY, Salameh JS, Mok J, Chew J, Sharma A, Leno-Duran E, Suzuki-Uematsu S, Suzuki N, Han SS, Lu FK, Ji M, Zhang R, Liu Y, Strominger J, Shneider NA, Petrucelli L, Xie XS, Eggan K Abstract The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics. PMID: 27796305 [PubMed - indexed for MEDLINE]
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Related Articles A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials. Sci Rep. 2017 04 07;7:45780 Authors: Eleuteri C, Olla S, Veroni C, Umeton R, Mechelli R, Romano S, Buscarinu MC, Ferrari F, Calò G, Ristori G, Salvetti M, Agresti C Abstract There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan. PMID: 28387380 [PubMed - indexed for MEDLINE]
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Related Articles Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair. Sci Rep. 2017 04 13;7(1):884 Authors: Garbuzova-Davis S, Kurien C, Thomson A, Falco D, Ahmad S, Staffetti J, Steiner G, Abraham S, James G, Mahendrasah A, Sanberg PR, Borlongan CV Abstract Vascular pathology, including blood-CNS barrier (B-CNS-B) damage via endothelial cell (EC) degeneration, is a recently recognized hallmark of Amyotrophic Lateral Sclerosis (ALS) pathogenesis. B-CNS-B repair may be a new therapeutic approach for ALS. This study aimed to determine effects of transplanted unmodified human bone marrow CD34+ (hBM34+) cells into symptomatic G93A mice towards blood-spinal cord barrier (BSCB) repair. Thirteen weeks old G93A mice intravenously received one of three different doses of hBM34+ cells. Cell-treated, media-treated, and control mice were euthanized at 17 weeks of age. Immunohistochemical (anti-human vWF, CD45, GFAP, and Iba-1) and motor neuron histological analyses were performed in cervical and lumbar spinal cords. EB levels in spinal cord parenchyma determined capillary permeability. Transplanted hBM34+ cells improved behavioral disease outcomes and enhanced motor neuron survival, mainly in high-cell-dose mice. Transplanted cells differentiated into ECs and engrafted within numerous capillaries. Reduced astrogliosis, microgliosis, and enhanced perivascular end-feet astrocytes were also determined in spinal cords, mostly in high-cell-dose mice. These mice also showed significantly decreased parenchymal EB levels. EC differentiation, capillary engraftment, reduced capillary permeability, and re-established perivascular end-feet astrocytes in symptomatic ALS mice may represent BSCB repair processes, supporting hBM34+ cell transplantation as a future therapeutic strategy for ALS patients. PMID: 28408761 [PubMed - indexed for MEDLINE]
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Related Articles Motoneuron Disease: Clinical. Adv Neurobiol. 2017;15:191-210 Authors: Ilieva H, Maragakis NJ Abstract ALS is a neurodegenerative disease in which the primary symptoms result in progressive neuromuscular weakness. Recent studies have highlighted that there is significant heterogeneity with regard to anatomical and temporal disease progression. Importantly, more recent advances in genetics have revealed new causative genes to the disease. New efforts have focused on the development of biomarkers that could aid in diagnosis, prognosis, and serve as pharmacodynamics markers. Although traditional pharmaceuticals continue to undergo trials for ALS, new therapeutic strategies including stem cell transplantation studies, gene therapies, and antisense therapies targeting some of the familial forms of ALS are gaining momentum. PMID: 28674982 [PubMed - indexed for MEDLINE]
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Related Articles Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis. Stem Cells. 2018 03;36(3):293-303 Authors: Serio A, Patani R Abstract Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS. Although animal models have proven invaluable in basic neuroscience research, a growing number of studies confirm fundamental interspecies differences between popular model organisms and the human condition. This may in part explain the failure of therapeutic translation from rodent preclinical models. It follows that integration of a human experimental model using patient-specific induced pluripotent stem cells may be necessary to capture the complexity of human neurodegeneration with fidelity. Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS. Such reductionist and integrated cross-modal approaches allow systematic elucidation of cell-autonomous and non-cell-autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention. Stem Cells 2018;36:293-303. PMID: 29235200 [PubMed - indexed for MEDLINE]
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Related Articles Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy. Mol Neurobiol. 2018 Aug 17;: Authors: Abati E, Bresolin N, Comi GP, Corti S Abstract Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders. PMID: 30120734 [PubMed - as supplied by publisher]
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Related Articles Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open Label Phase I Clinical Trial. Cell J. 2019 Jan;20(4):592-598 Authors: Nabavi SM, Arab L, Jarooghi N, Bolurieh T, Abbasi F, Mardpour S, Azimyian V, Moeininia F, Maroufizadeh S, Sanjari L, Hosseini SE, Aghdami N Abstract Objective: Amyotrophic lateral sclerosis (ALS) is the most severe disorder within the spectrum of motor neuron diseases (MND) that has no effective treatment and a progressively fatal outcome. We have conducted two clinical trials to assess the safety and feasibility of intravenous (IV) and intrathecal (IT) injections of bone marrow derived mesenchymal stromal cells (BM-MSCs) in patients with ALS. Materials and Methods: This is an interventional/experimental study. We enrolled 14 patients that met the following inclusion criteria: definitive diagnosis of sporadic ALS, ALS Functional Rating Scale (ALS-FRS) ≥24, and ≥40% predicted forced vital capacity (FVC). All patients underwent bone marrow (BM) aspiration to obtain an adequate sample for cell isolation and culture. Patients in group 1 (n=6) received an IV and patients in group 2 (n=8) received an IT injection of the cell suspension. All patients in both groups were followed at 24 hours and 2, 4, 6, and 12 months after the injection with ALS-FRS, FVC, laboratory tests, check list of side effects and brain/spinal cord magnetic resonance imaging (MRI). In each group, one patient was lost to follow up one month after cell injection and one patient from IV group died due to severe respiratory insufficiency and infection. Results: During the follow up there were no reports of adverse events in terms of clinical and laboratory assessments. In MRI, there was not any new abnormal finding. The ALS-FRS score and FVC percentage significantly reduced in all patients from both groups. Conclusion: This study has shown that IV and IT transplantation of BM-derived stromal cells is safe and feasible (Registration numbers: NCT01759797 and NCT01771640). PMID: 30124008 [PubMed]
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Related Articles Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. Nat Med. 2018 Oct;24(10):1579-1589 Authors: Fujimori K, Ishikawa M, Otomo A, Atsuta N, Nakamura R, Akiyama T, Hadano S, Aoki M, Saya H, Sobue G, Okano H Abstract Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models. PMID: 30127392 [PubMed - in process]
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Related Articles Intraspinal Transplantation of the Adipose Tissue-Derived Regenerative Cells in Amyotrophic Lateral Sclerosis in Accordance with the Current Experts' Recommendations: Choosing Optimal Monitoring Tools. Stem Cells Int. 2018;2018:4392017 Authors: Kuzma-Kozakiewicz M, Marchel A, Kaminska A, Gawel M, Sznajder J, Figiel-Dabrowska A, Nowak A, Maj E, Krzesniak NE, Noszczyk BH, Domanska-Janik K, Sarnowska A Abstract Stem cells (SCs) may constitute a perspective alternative to pharmacological treatment in neurodegenerative diseases. Although the safety of SC transplantation has been widely shown, their clinical efficiency in amyotrophic lateral sclerosis (ALS) is still to be proved. It is not only due to a limited number of studies, small treatment groups, and fast but nonlinear disease progression but also due to lack of objective methods able to show subtle clinical changes. Preliminary guidelines for cell therapy have recently been proposed by a group of ALS experts. They combine clinical, neurophysiological, and functional assessment together with monitoring of the cytokine level. Here, we describe a pilot study on transplantation of autologous adipose-derived regenerative cells (ADRC) into the spinal cord of the patients with ALS and monitoring of the results in accordance with the current recommendations. To show early and/or subtle changes within the muscles of interest, a wide range of clinical and functional tests were used and compared in order to choose the most sensitive and optimal set. Additionally, an analysis of transplanted ADRC was provided to develop standards ensuring the derivation and verification of adequate quality of transplanted cells and to correlate ADRC properties with clinical outcome. PMID: 30158984 [PubMed]
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Related Articles Maximizing the Survival of Amyotrophic Lateral Sclerosis Patients: Current Perspectives. Neurol Res Int. 2018;2018:6534150 Authors: Khairoalsindi OA, Abuzinadah AR Abstract Amyotrophic lateral sclerosis is a neurodegenerative disease that leads to loss of the upper and lower motor neurons. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. The disease has a poor prognosis, with only two disease-modifying drugs approved by the United States Food and Drug Administration (FDA). The approved drugs for the disease have very limited survival benefits. Edaravone is a new FDA-approved medication that may slow the disease progression by 33% in a selected subgroup of ALS patients. This paper covers the various interventions that may provide survival benefits, such as early diagnosis, medications, gene therapy, stem cell therapy, diet, nutritional supplements, multidisciplinary clinics, and mechanical invasive and noninvasive ventilation. The recent data on masitinib, the role of enteral feeding, gene therapy, and stem cell therapy is discussed. PMID: 30159171 [PubMed]
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Related Articles Chemical conversion of human and mouse fibroblasts into motor neurons. Sci China Life Sci. 2018 Oct;61(10):1151-1167 Authors: Qin H, Zhao A, Ma K, Fu X Abstract Transplantation of motor neurons can provide long-term functional benefits in animal models of neurodegenerative motor neuron diseases such as amyotrophic lateral sclerosis and traumatic spinal cord injury. Although embryonic stem cells can differentiate into motor neurons, alternative sources of motor neurons may be controllable for disease modeling and transplantation. Here, we show that human and mouse fibroblasts can be efficiently and directly converted into motor neurons by a cocktail of five small molecules, without the involvement of the neural progenitor stage. The chemically-induced motor neurons display the distinct neuronal morphology and express motor neuron markers. Interestingly, when the same chemical compounds were soaked in beads and implanted in the hypodermis of the back skins of mice, surrounding cells begin to express motor neuron markers, indicating in vivo motor neuron reprogramming. Taken together, we provide an efficient approach for chemically converting human and mouse fibroblasts into motor neurons suitable for cell replacement therapy and neurodegenerative disease modeling. PMID: 30159682 [PubMed - in process]
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Related Articles Stem cell therapy for neurological disorders: A focus on aging. Neurobiol Dis. 2018 Sep 13;: Authors: Nguyen H, Zarriello S, Coats A, Nelson C, Kingsbury C, Gorsky A, Rajani M, Neal EG, Borlongan CV Abstract Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options. PMID: 30219376 [PubMed - as supplied by publisher]
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Related Articles Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies. Cell Death Dis. 2018 Sep 17;9(10):937 Authors: Rosati J, Ferrari D, Altieri F, Tardivo S, Ricciolini C, Fusilli C, Zalfa C, Profico DC, Pinos F, Bernardini L, Torres B, Manni I, Piaggio G, Binda E, Copetti M, Lamorte G, Mazza T, Carella M, Gelati M, Valente EM, Simeone A, Vescovi AL Abstract Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that match foetal hNSCs and abide by cGMP standards, thus allowing clinical applications, has not been described. We generated hiNSCs by a virus-free technique, whose properties recapitulate those of the clinical-grade hNSCs successfully used in an Amyotrophic Lateral Sclerosis (ALS) phase I clinical trial. Ex vivo, hiNSCs critically depend on exogenous mitogens for stable self-renewal and amplification and spontaneously differentiate into astrocytes, oligodendrocytes and neurons upon their removal. In the brain of immunodeficient mice, hiNSCs engraft and differentiate into neurons and glia, without tumour formation. These findings now warrant the establishment of clinical-grade, autologous and continuous hiNSC lines for clinical trials in neurological diseases such as Huntington's, Parkinson's and Alzheimer's, among others. PMID: 30224709 [PubMed - in process]
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Related Articles Immunomodulatory Properties of Bone Marrow Mesenchymal Stem Cells from Patients with Amyotrophic Lateral Sclerosis and Healthy Donors. J Neuroimmune Pharmacol. 2018 Sep 21;: Authors: Javorkova E, Matejckova N, Zajicova A, Hermankova B, Hajkova M, Bohacova P, Kossl J, Krulova M, Holan V Abstract Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8+CD25+ lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4+FOXP3+ T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-α than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8+CD25+ and CD4+FOXP3+ T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8+CD25+ T lymphocytes) or even restriction (no increase of proportion of CD4+FOXP3+ T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. PMID: 30242613 [PubMed - as supplied by publisher]
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Related Articles Animal models of neurodegenerative diseases. Nat Neurosci. 2018 Oct;21(10):1370-1379 Authors: Dawson TM, Golde TE, Lagier-Tourenne C Abstract Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders. PMID: 30250265 [PubMed - in process]
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Related Articles Commentary on Some Recent Theses Relevant to Combating Aging: October 2018. Rejuvenation Res. 2018 Oct;21(5):482-487 Authors: Zealley B, de Grey ADNJ Abstract Theses reviewed in this issue include "Computational Pathology for Quantifying Spatial Heterogeneity in Digital Images of Tissue Sections from Solid Tumors," "Molecular Analysis of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Brain Tissue Identifies Disease Mechanisms Associated with Repetitive DNA Elements," "Neuroprotective Potential of the N-Terminal Beta Amyloid Peptide Fragment in the Neurodegeneration, Synaptic Dysfunction and Memory Deficits in Models of Alzheimer's Disease," "pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent," "Quantitative Approaches for Profiling the T Cell Receptor Repertoire in Human Tissues," and "Regulation and Repair of Neural Stem Cells and the Neurogenic Niche." PMID: 30255723 [PubMed - indexed for MEDLINE]
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Related Articles Astrocyte-based cell therapy: new hope for amyotrophic lateral sclerosis patients? Stem Cell Res Ther. 2018 Sep 26;9(1):241 Authors: Barbeito L Abstract Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease with no cure or treatment to stop disease progression. Because ALS represents an urgent unmet medical need, a significant number of therapeutics are being tested in preclinical and clinical studies. A recent publication in Stem Cell Research & Therapy by Izrael and colleagues reports about embryonic stem cell-derived astrocytes as a potential cell therapy for ALS. Such cells behave as highly trophic "young astrocytes", being able to delay disease onset and prolong survival when injected intrathechally in murine models of ALS overexpressing the SOD1G93A mutation. The safety and therapeutic potential of these cells are currently being evaluated in a clinical trial in ALS patients. This commentary discusses the mechanisms of action and potential therapeutic effects of these "young astrocytes" in ALS. PMID: 30257722 [PubMed - in process]
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Related Articles A Review of Stem Cell Therapy for Acquired Brain Injuries and Neurodegenerative Central Nervous System Diseases. PM R. 2018 Sep;10(9S2):S151-S156 Authors: Watanabe TK Abstract Cell-based therapies have been the subject of much discussion regarding their potential role in enhancing central nervous system function for a number of pathologic conditions. Much of the current research has been in preclinical trials, with clinical trials in the phase I or I/II stage. Nevertheless, there is considerable interest in the public about the potential regenerative role that stem cells may have in improving function for these neurologic conditions. This review will describe the different types of stem cells that are available, review their possible effects, and discuss some of the variables that investigators need to consider when designing their studies. Current clinical research in the areas of stroke, traumatic brain injury, and neurodegenerative diseases (amyotrophic lateral sclerosis and Parkinson disease) will be reviewed. As this article is aimed at a rehabilitation audience, outcome measures, and the role of concurrent rehabilitation therapies will also be mentioned. PMID: 30269801 [PubMed - in process]
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Related Articles Human neural stem cell transplantation improves cognition in a murine model of Alzheimer's disease. Sci Rep. 2018 Oct 03;8(1):14776 Authors: McGinley LM, Kashlan ON, Bruno ES, Chen KS, Hayes JM, Kashlan SR, Raykin J, Johe K, Murphy GG, Feldman EL Abstract Stem cell transplantation offers a potentially transformative approach to treating neurodegenerative disorders. The safety of cellular therapies is established in multiple clinical trials, including our own in amyotrophic lateral sclerosis. To initiate similar trials in Alzheimer's disease, efficacious cell lines must be identified. Here, we completed a preclinical proof-of-concept study in the APP/PS1 murine model of Alzheimer's disease. Human neural stem cell transplantation targeted to the fimbria fornix significantly improved cognition in two hippocampal-dependent memory tasks at 4 and 16 weeks post-transplantation. While levels of synapse-related proteins and cholinergic neurons were unaffected, amyloid plaque load was significantly reduced in stem cell transplanted mice and associated with increased recruitment of activated microglia. In vitro, these same neural stem cells induced microglial activation and amyloid phagocytosis, suggesting an immunomodulatory capacity. Although long-term transplantation resulted in significant functional and pathological improvements in APP/PS1 mice, stem cells were not identified by immunohistochemistry or PCR at the study endpoint. These data suggest integration into native tissue or the idea that transient engraftment may be adequate for therapeutic efficacy, reducing the need for continued immunosuppression. Overall, our results support further preclinical development of human neural stem cells as a safe and effective therapy for Alzheimer's disease. PMID: 30283042 [PubMed - in process]
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Related Articles Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci Adv. 2018 Oct;4(10):eaat5847 Authors: Osaki T, Uzel SGM, Kamm RD Abstract Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)-derived and light-sensitive channelrhodopsin-2-induced MN spheroids from a patient with sporadic ALS. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein-43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates. PMID: 30324134 [PubMed - in process]
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Related Articles Amyotrophic Lateral Sclerosis: An Update for 2018. Mayo Clin Proc. 2018 Nov;93(11):1617-1628 Authors: Oskarsson B, Gendron TF, Staff NP Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies. PMID: 30401437 [PubMed - in process]
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Related Articles Aggregated SOD1 causes selective death of cultured human motor neurons. Sci Rep. 2018 Nov 06;8(1):16393 Authors: Benkler C, O'Neil AL, Slepian S, Qian F, Weinreb PH, Rubin LL Abstract Most human neurodegenerative diseases share a phenotype of neuronal protein aggregation. In Amyotrophic Lateral Sclerosis (ALS), the abundant protein superoxide dismutase (SOD1) or the TAR-DNA binding protein TDP-43 can aggregate in motor neurons. Recently, numerous studies have highlighted the ability of aggregates to spread from neuron to neuron in a prion-like fashion. These studies have typically focused on the use of neuron-like cell lines or neurons that are not normally affected by the specific aggregated protein being studied. Here, we have investigated the uptake of pre-formed SOD1 aggregates by cultures containing pluripotent stem cell-derived human motor neurons. We found that all cells take up aggregates by a process resembling fluid-phase endocytosis, just as found in earlier studies. However, motor neurons, despite taking up smaller amounts of SOD1, were much more vulnerable to the accumulating aggregates. Thus, the propagation of disease pathology depends less on selective uptake than on selective response to intracellular aggregates. We further demonstrate that anti-SOD1 antibodies, being considered as ALS therapeutics, can act by blocking the uptake of SOD1, but also by blocking the toxic effects of intracellular SOD1. This work demonstrates the importance of using disease relevant cells even in studying phenomena such as aggregate propagation. PMID: 30401824 [PubMed - in process]
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Related Articles Reduced SIRT1/AMPK in Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stem Cells can be restored by resveratrol. J Tissue Eng Regen Med. 2018 Nov 26;: Authors: Yun YC, Jeong SG, Kim SH, Cho GW Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neuron system. Our previous study has shown that bone marrow-mesenchymal stem cells (BM-MSCs) from ALS patients have functional limitations in releasing neurotrophic factors and exhibit the senescence phenotype. In this study, we examined SIRT1/AMPK activities and identified significant decreases in the ALS-MSCs compared to normal healthy control originated BM-MSCs. This decline was restored by pre-treatment with resveratrol (RSV), measured using quantitative PCR, NAD/NADH assay, and immunoblot analysis. Neuro-progenitor markers were increased in RSV treated ALS-MSCs (RSV/ALS-MSCs). The differentiated ALS-MSCs exhibited a cell body and dendritic shape similar to neurons. RSV/ALS-MSCs showed significantly increased differentiation rate as compared to the untreated differentiated ALS-MSCs (ALS-dMSCs). The neurite numbers and lengths were also significantly increased. This was confirmed with immunoblot analysis using neuron specific markers such as nestin, NF-M, Tuj-1, and Map-2 in RSV/ALS-dMSCs. Thus, this study shows that ALS-MSCs showed down-regulation of AMPK/SIRT1 signaling, which was recovered by treatment with RSV. This data suggest that RSV can be one of candidate agents for improving therapeutic efficacy of ALS patients' originated MSCs. PMID: 30479062 [PubMed - as supplied by publisher]
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