Strategies for the Development of Cell Lines for Ex Vivo Gene Therapy in the Central Nervous System

Mejía-Toiber, Jana; Castillo, Claudia G.; Giordano, Magda

doi:10.3727/096368910x546599

Cited by 13 publications

(4 citation statements)

References 222 publications

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“…Several groups have attempted to increase therapeutic potential of MSCs by expressing different genes (43–45). The aim is to enhance the homing capacity and increase the immunomodulatory and neuroregenerative potential of MSCs by delivering new therapeutic agents to areas of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis

et al. 2013

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Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) asa therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation,lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.

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Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis

et al. 2013

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“…A therapeutic potential of bone marrow-derived microglia was also suggested for the treatment of high-grade glioma, severe combined immunodeficiency, multiple sclerosis, and other CNS pathologies (6). Despite the high therapeutic potential of BMDCs for cerebral pathologies (13) and an inestimable tool to study microglial biology, the mechanisms by which they enter the brain are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of Myeloablation, Peripheral Chimerism, and Whole-Body Irradiation on the Entry of Bone Marrow-Derived Cells into the Brain

2012

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Understanding how bone marrow-derived cells (BMDCs) enter the central nervous system (CNS) is critical for the development of therapies for brain-related disorders using hematopoietic stem cells. We investigated the brain damages and blood-brain barrier (BBB) modification following either whole-body irradiation or a myeloablative chemotherapy regimen in mice, and the capacity for these treatments to induce the entry of BMDCs into the CNS. Neither treatment had a lasting effect on brain integrity and both were equally efficient at achieving myeloablation. Injection of bone marrow cells from green fluorescent protein (GFP) transgenic mice was able to completely repopulate the hematopoietic niche in the circulation and in hematopoietic organs (thymus and spleen). However, GFP + cells only entered the brain following whole-body irradiation. We conclude that myeloablation, damages to the brain integrity, or the BBB and peripheral chimerism are not responsible for the entry of BMDCs into the CNS following irradiation.Key words: Microglia; Central nervous sysem (CNS); Neuroimmunology; Hematopoietic stem cell; Irradiation; Chemotherapy; Bone marrow-derived cells; Innate immunity INTRODUCTIONof high-grade glioma, severe combined immunodeficiency, multiple sclerosis, and other CNS pathologies (6). Despite the high therapeutic potential of BMDCs for Brain-specific macrophages called microglia are responsible for the immune defense of the brain through cerebral pathologies (13) and an inestimable tool to study microglial biology, the mechanisms by which they innate immunity processes (19). They are the only brain cell type deriving from bone marrow resident hematoenter the brain are poorly understood. Chimerism is the process by which injected bone poietic stem cells (18,22). The recruitment of bone marrow-derived cells (BMDCs) into the brain is highly marrow cells from a donor take over the hematopoietic system of a recipient. The use of the green fluorescent active throughout the embryonic life during which microglia populate the central nervous system (CNS) protein heterozygous (GFP +/− ) transgenic mouse model has eased the study of chimerism by facilitating the (5). It appears to be marginal during the adult life, as self-renewal of microglia could be sufficient to maintain tracking of injected GFP + cells in a GFP − background. Numerous models have been designed to induce chimethe microglial population (1), and more active in pathological conditions such as Alzheimer's disease (8). It rism in mouse models such as parabiosis, immunosuppression of the recipient mice, and irradiation of the was demonstrated that following whole-body irradiation, bone marrow transplantation was highly efficient to whole body, only the head, or the body with a protected head (24). It appears that only lethal doses of wholerestrict amyloid plaque formation and resolve the cognitive declines of mouse models of Alzheimer's disease body irradiation are able to create an efficient chimerism and to induce migrations of BMDCs to the brain. Con-...

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“…Neurodegenerative diseases have a potentially disastrous impact on quality of life, so ongoing efforts to develop novel therapeutic drug candidates are of utmost importance 99,[110][111][112][113] . The use of genetic manipulation in cell systems and nonhuman animal models may not predict the potential toxicity and lack of efficacy accurately in humans 85 .…”

Section: Resultsmentioning

confidence: 99%

Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis

et al. 2018

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Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.

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Strategies for the Development of Cell Lines for Ex Vivo Gene Therapy in the Central Nervous System

Cited by 13 publications

References 222 publications

Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis

Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis

Effects of Myeloablation, Peripheral Chimerism, and Whole-Body Irradiation on the Entry of Bone Marrow-Derived Cells into the Brain

Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis

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