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1.
Nat Commun ; 13(1): 4655, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945193

RESUMO

Friedreich's ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cell (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G-CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.


Assuntos
Ataxia de Friedreich , Fator Estimulador de Colônias de Granulócitos , Proteínas Recombinantes , Ataxia de Friedreich/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Granulócitos/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Projetos Piloto , Proteínas Recombinantes/efeitos adversos
2.
J Neurol Neurosurg Psychiatry ; 92(3): 295-302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33184094

RESUMO

OBJECTIVE: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). METHODS: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. RESULTS: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. CONCLUSIONS: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.


Assuntos
Reposicionamento de Medicamentos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Animais , Avaliação de Medicamentos , Humanos
3.
Brain Pathol ; 30(6): 1041-1055, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32580238

RESUMO

SAFB1 is a DNA and RNA binding protein that is highly expressed in the cerebellum and hippocampus and is involved in the processing of coding and non-coding RNAs, splicing and dendritic function. We analyzed SAFB1 expression in the post-mortem brain tissue of spinocerebellar ataxia (SCA), Huntington's disease (HD), Multiple sclerosis (MS), Parkinson's disease patients and controls. In SCA cases, the expression of SAFB1 in the nucleus was increased and there was abnormal and extensive expression in the cytoplasm where it co-localized with the markers of Purkinje cell injury. Significantly, no SAFB1 expression was found in the cerebellar neurons of the dentate nucleus in control or MS patients; however, in SCA patients, SAFB1 expression was increased significantly in both the nucleus and cytoplasm of dentate neurons. In HD, we found that SAFB1 expression was increased in the nucleus and cytoplasm of striatal neurons; however, there was no SAFB1 staining in the striatal neurons of controls. In PD substantia nigra, we did not see any changes in neuronal SAFB1 expression. iCLIP analysis found that SAFB1 crosslink sites within ATXN1 RNA were adjacent to the start and within the glutamine repeat sequence. Further investigation found increased binding of SAFB1 to pathogenic ATXN1-85Q mRNA. These novel data strongly suggest SAFB1 contributes to the etiology of SCA and Huntington's chorea and that it may be a pathological marker of polyglutamine repeat expansion diseases.


Assuntos
Encéfalo/metabolismo , Doença de Huntington/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neurônios/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Receptores de Estrogênio/metabolismo , Ataxias Espinocerebelares/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Feminino , Humanos , Doença de Huntington/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia
4.
JAMA ; 321(2): 175-187, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30644981

RESUMO

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure: Conversion to objectively defined secondary progressive MS. Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.


Assuntos
Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Alemtuzumab/uso terapêutico , Estudos de Coortes , Progressão da Doença , Feminino , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Interferon beta/uso terapêutico , Masculino , Natalizumab/uso terapêutico , Tempo para o Tratamento
5.
J Pathol ; 247(4): 422-434, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30565681

RESUMO

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , PPAR alfa/metabolismo , RNA Interferente Pequeno/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes/métodos , Humanos , Lentivirus , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Fenótipo , Transdução de Sinais/fisiologia , Transplante Heterólogo , Células Tumorais Cultivadas
6.
Stem Cells Transl Med ; 7(10): 748-758, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30063300

RESUMO

The potential of autologous cell-based therapies including those using multipotent mesenchymal stromal cells (MSCs) is being investigated for multiple sclerosis (MS) and other neurological conditions. However, the phenotype of MSC in neurological diseases has not been fully characterized. We have previously shown that MSC isolated from patients with progressive MS (MS-MSC) have reduced expansion potential, premature senescence, and reduced neuroprotective potential in vitro. In view of the role of antioxidants in ageing and neuroprotection, we examined the antioxidant capacity of MS-MSC demonstrating that MS-MSC secretion of antioxidants superoxide dismutase 1 (SOD1) and glutathione S-transferase P (GSTP) is reduced and correlates negatively with the duration of progressive phase of MS. We confirmed reduced expression of SOD1 and GSTP by MS-MSC along with reduced activity of SOD and GST and, to examine the antioxidant capacity of MS-MSC under conditions of nitrosative stress, we established an in vitro cell survival assay using nitric oxide-induced cell death. MS-MSC displayed differential susceptibility to nitrosative stress with accelerated senescence and greater decline in expression of SOD1 and GSTP in keeping with reduced expression of master regulators of antioxidant responses nuclear factor erythroid 2-related factor 2 and peroxisome proliferator-activated receptor gamma coactivator 1-α. Our results are compatible with dysregulation of antioxidant responses in MS-MSC and have significant implications for development of autologous MSC-based therapies for MS, optimization of which may require that these functional deficits are reversed. Furthermore, improved understanding of the underlying mechanisms may yield novel insights into MS pathophysiology and biomarker identification. Stem Cells Translational Medicine 2018;7:748-758.


Assuntos
Antioxidantes/metabolismo , Células-Tronco Mesenquimais/metabolismo , Esclerose Múltipla/patologia , Células da Medula Óssea/citologia , Senescência Celular/efeitos dos fármacos , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Esclerose Múltipla/terapia , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Nitrosos/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
7.
Pract Neurol ; 18(6): 472-476, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29848512

RESUMO

Given the intuitive potential of stem cell therapy and limitations of current treatment options for progressive multiple sclerosis (MS), it is not surprising that patients consider undertaking significant clinical and financial risks to access stem cell transplantation. However, while increasing evidence supports autologous haematopoietic stem cell transplantation (AHSCT) in aggressive relapsing-remitting MS, interventions employing haematopoietic or other stem cells should otherwise be considered experimental and recommended only in the context of a properly regulated clinical study. Understandably, most neurologists are unfamiliar with AHSCT procedures and the specific requirements for quality assurance and safety standards, as well as post-procedure precautions and follow-up. Consequently they may feel ill-equipped to advise patients. Here, we highlight important points for discussion in consultations with patients considering stem cell 'tourism' for MS.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Esclerose Múltipla/psicologia , Esclerose Múltipla/cirurgia , Neurologistas/psicologia , Humanos
8.
Acta Neuropathol ; 135(6): 907-921, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29541917

RESUMO

Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Here we report, for the first time, that fusion of a bone marrow-derived cell with a neuron in vivo, in the mature brain, results in the formation of a spontaneously firing neuron. Notably, we also provide evidence supporting the concept that heterotypic cell fusion acts as a biological mechanism to repair pathological changes in Purkinje cell structure and electrophysiology. We induced chronic central nervous system inflammation in chimeric mice expressing bone marrow cells tagged with enhanced green fluorescent protein. Subsequent in-depth histological analysis revealed significant Purkinje cell injury. In addition, there was an increased incidence of cell fusion between bone marrow-derived cells and Purkinje cells, revealed as enhanced green fluorescent protein-expressing binucleate heterokaryons. These fused cells resembled healthy Purkinje cells in their morphology, soma size, ability to synthesize the neurotransmitter gamma-aminobutyric acid, and synaptic innervation from neighbouring cells. Extracellular recording of spontaneous firing ex vivo revealed a shift in the predominant mode of firing of non-fused Purkinje cells in the context of cerebellar inflammation. By contrast, the firing patterns of fused Purkinje cells were the same as in healthy control cerebellum, indicating that fusion of bone marrow-derived cells with Purkinje cells mitigated the effects of cell injury on electrical activity. Together, our histological and electrophysiological results provide novel fundamental insights into physiological processes by which nerve cells are protected in adult life.


Assuntos
Células da Medula Óssea/fisiologia , Transplante de Medula Óssea , Encefalomielite Autoimune Experimental/fisiopatologia , Encefalomielite Autoimune Experimental/terapia , Células de Purkinje/fisiologia , Potenciais de Ação/fisiologia , Animais , Células da Medula Óssea/patologia , Fusão Celular , Quimera , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Bainha de Mielina/patologia , Bainha de Mielina/fisiologia , Neuroproteção/fisiologia , Células de Purkinje/patologia , Técnicas de Cultura de Tecidos
9.
Ann Neurol ; 83(4): 779-793, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29534309

RESUMO

OBJECTIVE: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease. METHODS: Mice received a transplant of fluorescently tagged sex-mismatched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests. At 6 months post-transplant, mice were euthanized for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a subgroup of transplanted mice also received monthly subcutaneous infusions of the cytokines granulocyte-colony stimulating factor and stem cell factor. RESULTS: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and antioxidant defenses were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells, and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected after cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident. INTERPRETATION: Our data provide proof of concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. Ann Neurol 2018;83:779-793.


Assuntos
Transplante de Medula Óssea/métodos , Ataxia de Friedreich/cirurgia , Animais , Peso Corporal/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Ataxia de Friedreich/genética , Gânglios Espinais/patologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Ligação ao Ferro/genética , Leucócitos Mononucleares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/fisiologia , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Frataxina
10.
J Clin Pathol ; 71(8): 695-701, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29463577

RESUMO

AIMS: Histopathological tissue samples are being increasingly used as sources of nucleic acids in molecular pathology translational research. This study investigated the suitability of glioblastoma and control central nervous system (CNS) formalin-fixed paraffin embedded (FFPE) tissue-derived RNA for gene expression analyses. METHODS: Total RNA was extracted from control (temporal lobe resection tissue) and glioblastoma FFPE tissue samples. RNA purity (260/280 ratios) was determined and RNA integrity number (RIN) analysis was performed. RNA was subsequently used for RT-qPCR for two reference genes, 18S and GAPDH. RESULTS: Reference gene expression was equivalent between control and glioblastoma tissue when using RNA extracted from FFPE tissue, which has key implications for biological normalisation for CNS gene expression studies. There was a significant difference between the mean RIN values of control and glioblastoma FFPE tissue. There was no significant correlation between 260/280 or RIN values versus total RNA yield. The age of the tissue blocks did not influence RNA yield, fragmentation or purity. There was no significant correlation between RIN or 260/280 ratios and mean qPCR cycle threshold for either reference gene. CONCLUSIONS: This study showed that routinely available CNS FFPE tissue is suitable for RNA extraction and downstream gene expression studies, even after 60 months of storage. Substantial RNA fragmentation associated with glioblastoma and control FFPE tissue blocks did not preclude downstream RT-qPCR gene expression analyses. Cross validation with both archival and prospectively collated FFPE specimens is required to further demonstrate that CNS tissue blocks can be used in novel translational molecular biomarker studies.


Assuntos
Neoplasias Encefálicas/genética , Epilepsia do Lobo Temporal/genética , Fixadores/química , Formaldeído/química , Perfilação da Expressão Gênica , Glioblastoma/genética , Inclusão em Parafina , Estabilidade de RNA , RNA Neoplásico/genética , Fixação de Tecidos/métodos , Neoplasias Encefálicas/cirurgia , Estudos de Casos e Controles , Epilepsia do Lobo Temporal/cirurgia , Perfilação da Expressão Gênica/normas , Glioblastoma/cirurgia , Humanos , Inclusão em Parafina/normas , Valor Preditivo dos Testes , Controle de Qualidade , Reprodutibilidade dos Testes , Fatores de Tempo , Fixação de Tecidos/normas
11.
Cytotherapy ; 20(1): 21-28, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28917625

RESUMO

BACKGROUND: Clinical trials using ex vivo expansion of autologous mesenchymal stromal cells (MSCs) are in progress for several neurological diseases including multiple sclerosis (MS). Given that environment alters MSC function, we examined whether in vitro expansion, increasing donor age and progressive MS affect the neuroprotective properties of the MSC secretome. METHODS: Comparative analyses of neuronal survival in the presence of MSC-conditioned medium (MSCcm) isolated from control subjects (C-MSCcm) and those with MS (MS-MSCcm) were performed following (1) trophic factor withdrawal and (2) nitric oxide-induced neurotoxicity. RESULTS: Reduced neuronal survival following trophic factor withdrawal was seen in association with increasing expansion of MSCs in vitro and MSC donor age. Controlling for these factors, there was an independent, negative effect of progressive MS. In nitric oxide neurotoxicity, MSCcm-mediated neuroprotection was reduced when C-MSCcm was isolated from higher-passage MSCs and was negatively associated with increasing MSC passage number and donor age. Furthermore, the neuroprotective effect of MSCcm was lost when MSCs were isolated from patients with MS. DISCUSSION: Our findings have significant implications for MSC-based therapy in neurodegenerative conditions, particularly for autologous MSC therapy in MS. Impaired neuroprotection mediated by the MSC secretome in progressive MS may reflect reduced reparative potential of autologous MSC-based therapy in MS and it is likely that the causes must be addressed before the full potential of MSC-based therapy is realized. Additionally, we anticipate that understanding the mechanisms responsible will contribute new insights into MS pathogenesis and may also be of wider relevance to other neurodegenerative conditions.


Assuntos
Envelhecimento/patologia , Progressão da Doença , Células-Tronco Mesenquimais/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Fármacos Neuroprotetores/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Humanos , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Óxido Nítrico/metabolismo
12.
Mult Scler ; 24(7): 919-931, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28548004

RESUMO

BACKGROUND: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. OBJECTIVES: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. METHODS: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. RESULTS: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of ß-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. CONCLUSION: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS.


Assuntos
Proliferação de Células , Senescência Celular , Células-Tronco Mesenquimais/patologia , Esclerose Múltipla/patologia , Adulto , Proliferação de Células/fisiologia , Células Cultivadas , Senescência Celular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nicho de Células-Tronco/fisiologia
13.
Curr Treat Options Neurol ; 19(12): 47, 2017 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-29177818

RESUMO

Purpose of review The purpose of this review is to assess the evidence behind treatment regimens for cerebellar ataxias occurring in the context of systemic disease. We will address systemic conditions which are associated with specific involvement of the cerebellum (rather than widespread nervous system involvement) and those conditions for which some degree of evidence of treatment response exists. Recent findings We have divided systemic disorders affecting the cerebellum into systemic immunological disorders, endocrine and metabolic disorders and paraneoplastic. Recent studies have increased understanding of the range of cerebellar disorders associated with a systemic immunological condition. The identification of newer pathogenic antibodies has improved diagnosis in conditions which would have previously been labelled as idiopathic. However, their rarity and phenotypic variability makes defining optimal immunomodulatory treatment regimens challenging. There is some evidence for beneficial effects of immunomodulation, particularly in anti-GAD ataxia and Hashimoto's encephalopathy, although, at this time, specific treatment regimens cannot be defined. Immune-mediated paraneoplastic cerebellar disorders show response to therapy dependent, to some extent, on the underlying pathogenic antibody. Much is still to be understood concerning treatment regimens for the ataxic manifestations of metabolic disorders, notably alcohol-induced cerebellar injury, which are common and which are associated with significant disability. Summary Despite their rarity, cerebellar ataxias occurring in the context of systemic disease cause significant morbidity and better therapies are required to improve outcomes associated with these conditions.

14.
J Alzheimers Dis ; 60(4): 1511-1524, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29060936

RESUMO

Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-ß protein precursor (AßPP), and amyloid-ß (Aß) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AßPP and soluble Aß in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.


Assuntos
Doença de Alzheimer/metabolismo , Lobo Frontal/metabolismo , Cinesinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Precursor de Proteína beta-Amiloide/metabolismo , Western Blotting , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima , Proteínas tau/metabolismo
15.
Biomark Med ; 11(8): 589-591, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28770630
16.
Front Neurol ; 8: 312, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28701995

RESUMO

Multiple sclerosis (MS) commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs contribute significantly to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are particularly difficult to treat. Increasing knowledge concerning the pathophysiology of cerebellar disease in MS from human postmortem studies, experimental models, and clinical trials has raised the hope that cerebellar symptoms will be better treated in the future.

17.
Cerebellum ; 16(4): 840-851, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28456899

RESUMO

Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia.


Assuntos
Ataxia de Friedreich/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Células-Tronco Mesenquimais/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Fêmur , Técnicas de Silenciamento de Genes , Homeostase/fisiologia , Humanos , Peróxido de Hidrogênio/metabolismo , Proteínas de Ligação ao Ferro/genética , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , RNA Interferente Pequeno , Células de Schwann/metabolismo , Frataxina
18.
Lancet Neurol ; 16(3): 172-173, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28229881

Assuntos
Nervo Óptico
19.
Lancet Neurol ; 16(4): 271-281, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28209331

RESUMO

BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006). INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. FUNDING: National Health and Medical Research Council, and the University of Melbourne.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Adulto , Alemtuzumab , Estudos de Coortes , Bases de Dados Bibliográficas/estatística & dados numéricos , Avaliação da Deficiência , Feminino , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
20.
Histopathology ; 70(7): 1030-1043, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27926792

RESUMO

AIMS: PPARα agonists are in current clinical use as hypolipidaemic agents and show significant antineoplastic effects in human glioblastoma models. To date however, the expression of PPARα in large-scale glioblastoma datasets has not been examined. We aimed to investigate the expression of the transcription factor PPARα in primary glioblastoma, the relationship between PPARα expression and patients' clinicopathological features and other molecular markers associated with gliomagenesis. METHODS AND RESULTS: With protein immunoblotting techniques and reverse transcription quantitative real-time PCR, PPARα was found to be significantly overexpressed in glioblastoma compared with control brain tissue (P = 0.032 and P = 0.005). PPARA gene expression was found to be enriched in the classical glioblastoma subtype within The Cancer Genome Atlas (TCGA) dataset. Although not associated with overall survival when assessed by immunohistochemistry, cross-validation with the TCGA dataset and multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (P = 0.042). Finally, hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4, and NTRK2. CONCLUSIONS: PPARα is overexpressed in primary glioblastoma and high PPARA expression functions as an independent prognostic marker in the glioblastoma TCGA dataset. Further studies are required to explore genetic associations with high PPARA expression and to analyse the predictive role of PPARα expression in glioblastoma models in response to PPARα agonists.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , PPAR alfa/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Criança , Feminino , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PPAR alfa/análise , Prognóstico , Modelos de Riscos Proporcionais
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