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Safety of intrathecal injection of Wharton's jellyderived mesenchymal stem cells in amyotrophic lateral sclerosis therapy

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Neural Regeneration Research 2019年第2期14卷 313-318页

作者： Monika Barczewska Mariusz Grudniak Stanis?aw Maksymowicz Tomasz Siwek Tomasz O?dak Katarzyna Jezierska-Wo?niak Dominika G?adysz Wojciech Maksymowicz Department of Neurology and Neurosurgery School of Medicine Collegium Medicum-University of Warmia and Mazury in Olsztyn University Clinical Hospital in Olsztyn Instytut Terapii Komórkowych w Olsztynie(Cell Therapies Institute FamiCord Group) Polski Bank Komórek Macierzystych (PBKM FamiCord Group) Department of Psychology Clinical Logopedics and Social Science in Medicine Faculty of Health Sciences Collegium Medicum-University of Warmia and Mazury in Olsztyn Department of Neurology and Neurosurgery Laboratory of Regenerative Medicine School of Medicine Collegium Medicum-University of Warmia and Mazury in Olsztyn

Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.

关键词： amyotrophic lateral sclerosis stem cells therapy intrathecal injections Wharton's jelly-derived mesenchymal stem cells adverse events safety cerebrospinal fluid neural regeneration

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Poly-PR in C9ORF72-Related Amyotrophic Lateral sclerosis/Frontotemporal Dementia Causes Neurotoxicity by Clathrin-Dependent Endocytosis

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Neuroscience Bulletin 2019年第5期35卷 889-900页

作者： Rui Wang Xingyun Xu Zongbing Hao Shun Zhang Dan Wu Hongyang Sun Chenchen Mu Haigang Ren Guanghui Wang Laboratory of Molecular Neuropathology Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology College of Pharmaceutical SciencesSoochow University

GGGGCC repeat expansions in the C9 ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia(c9 ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9 ORF72 produce five dipeptide repeat(DPR) proteins by an unconventional repeat-associated non-ATG(RAN)translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs(poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5 Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase(JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PRinduced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependentendocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.

关键词： Amyotrophic lateral sclerosis C9ORF72 Poly-PR Clathrin ER stress

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Monitoring Value of Multimodal Magnetic Resonance Imaging in Disease Progression of Amyotrophic Lateral sclerosis: A Prospective Observational Study

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Chinese Medical Journal 2018年第24期131卷 2904-2909页

作者： Dong-Chao Shen Yin-Yan Xu Bo Hou Hong-Fei Tai Kang Zhang Shuang-Wu Liu Zhi-Li Wang Feng Feng Ming-Sheng Liu Li-Ying Cui Department of Neurology Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijing 100730China Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730China Department of Radiology Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijing 100730China Neuroscience Center Chinese Academy of Medical SciencesBeijing 100730China

Background: Ongoing efforts have been made to identify new neuroimaging markers to track amyotrophic lateral sclerosis (ALS) progression. This study aimed to explore the monitoring value of multimodal magnetic resonance imaging (MRI) in the disease progression of ALS. Methods: From September 2015 to March 2017, ten patients diagnosed with ALS in Peking Union Medical College Hospital completed head MRI scans at baseline and during follow-up. Multimodal MRI analyses, including gray matter (GM) volume measured by voxel-based morphometry;cerebral blood flow (CBF) evaluated by arterial spin labeling;functional connectivity, including low-frequency fluctuation (fALFF) and regional homogeneity (ReHo), measured by resting-state functional MRI;and integrity of white-matter (WM) fiber tracts evaluated by diffusion tensor imaging, were performed in these patients. Comparisons of imaging metrics were made between baseline and follow-up using paired t-test. Results: In the longitudinal comparisons, the brain structure (GM volume of the right precentral gyri, left postcentral gyri, and right thalami) and perfusion (CBF of the bilateral temporal poles, left precentral gyri, postcentral gyri, and right middle temporal gyri) in both motor and extramotor areas at follow-up were impaired to different extents when compared with those at baseline (all P < 0.05, false discovery rate adjusted). Functional connectivity was increased in the motor areas (fALFF of the right precentral gyri and superior frontal gyri, and ReHo of right precentral gyri) and decreased in the extramotor areas (fALFF of the bilateral middle frontal gyri and ReHo of the right precuneus and cingulate gyri) (all P < 0.001, unadjusted). No significant changes were detected in terms of brain WM measures. Conclusion: Multimodal MRI could be used to monitor short-term brain changes in ALS patients.

关键词： Amyotrophic Lateral sclerosis Disease Progression Monitoring Value Multimodal Magnetic Resonance Imaging

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Study on variation trend of repetitive nerve stimulation waveform in amyotrophic lateral sclerosis

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Chinese Medical Journal 2019年第5期132卷 542-550页

作者： Li-Lan Fu He-Xiang Yin Ming-Sheng Liu Li-Ying Cui Department of Neurology Peking Union Medical College Hospital Chinese Academy of Medical Sciences Beijing 100730 China Neurosciences Center Chinese Academy of Medical Sciences Beijing 100730China

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower neurons with no effective cure. Electrophysiological studies have found decremental responses during low-frequency repetitive nerve stimulation (RNS) except for diffused neurogenic activities. However, the difference between ALS and generalized myasthenia gravis (GMG) in terms of waveform features is unclear. In the current study, we explored the variation trend of the amplitudes curve between ALS and GMG with low-frequency, positive RNS, and the possible mechanism is discussed preliminarily. Methods: A total of 85 ALS patients and 41 GMG patients were recruited. All patients were from Peking Union Medical College Hospital (PUMCH) between July 1,2012 and February 28,2015. RNS study included ulnar nerve, accessory nerve and facial nerve at 3 Hz and 5 Hz stimulation. The percentage reduction in the amplitude of the fourth or fifth wave from the first wave was calculated and compared with the normal values of our hospital. A 15% decrease in amplitude is defined as a decrease in amplitude. Results: The decremental response at low-frequency RNS showed the abnormal rate of RNS decline was 54.1%(46/85) in the ALS group, and the results of different nerves were 54.1 %(46/85) of the accessory nerve, 8.2%(7/85) of the ulnar nerve and 0%(0/85) of the facial nerve stimulation, respectively. In the GMG group, the abnormal rate of RNS decline was 100%(41/41) at low-frequency RNS of accessory nerves. However, there was a significant difference between the 2 groups in the amplitude after the sixth wave. Conclusions: Both groups of patients are able to show a decreasing amplitude of low-frequency stimulation RNS, but the recovery trend after the sixth wave has significant variation. It implies the different pathogenesis of NMJ dysfunction of these 2 diseases.

关键词： Amyotrophic lateral sclerosis Generalized myasthenia gravis Neuromuscular junction Repetitive nerve stimulation

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On the road to new treatments for multiple sclerosis: targeting dendritic cell migration into the central nervous system

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Neural Regeneration Research 2019年第12期14卷 2088-2090页

作者： Megha Meena Nathalie Cools Laboratory of Experimental Hematology Vaccine & Infectious Disease Institute (VAXINFECTIO) Faculty of Medicine and Health Sciences University of Antwerp

Distinct migratory pathways and trafficking of dendritic cells to the central nervous system (CNS): The immune system is a host defense mechanism protecting against invaders, such as bacteria and viruses, while maintaining tolerance to self. Nonetheless, a few sites throughout the body are believed to be immunologically inert, such as the testes, the eye and the brain. Indeed, experiments in the mid-20th century gave rise to the concept of the brain as a site of immune privilege. Originally, the immune privilege of the brain was thought to be absolute, attributed by a physical blood-brain barrier (BBB) protecting the CNS from the entry of pathogens and circulating immune cells. These views have changed and currently, the CNS is seen as an immune-specialized site regulated by immunological components into and within the CNS.

关键词： new treatments multiple sclerosis nervous system

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The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

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Cellular & Molecular Immunology 2015年第6期12卷 777-779页

作者： Jose AG Agundez Elena Garcia-Martin Carmen Martinez Julian Benito-Leon Julian Benito-Leon Jorge Millan-PascualMaria Diaz-Sanchez Patricia Calleja Diana Pisa Laura Turpin-Fenoll Hortensia Alonso-Navarro Lucia Ayuso-Peralta Dolores Torrecillas Esteban Garcla-Albea Jose Francisco Plaza-Nieto Felix Javier Jimenez-Jimenez Department of Pharmacology University of Extremadura CAceres Spain Department of Biochemistry and Molecular Biology University of Extremadura Caceres Spain CiBERNED Centro de InvestigaciOn BiomEdica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos III Spain Service of Neurology Hospital Universitario Doce de Octubre Madrid Spain Department of Medicine University Complutense Madrid Spain Section of Neurology Hospital La Mancha-Centro Alcazar de San Juan (Ciudad Real) Spain Centro de Biologfa Molecular Severo Ochoa (CSIC-UAM) Facultad de Ciencias Universidad Autonoma Cantoblanco 28049 Madrid Spain Department of Medicine-Neurology Hospital 'Principe de Asturias' Universidad de Alcala Alcala de Henares (Madrid) Spain Section of Neurology Hospital Universitario del Sureste Arganda del Rey (Madrid) Spain Correspondence: Dr FJ Jimenez-Jimenez C/Marroquina 14 3° B E-28030 Madrid Spain.

We analyzed the allelic and genotypic frequencies of the glutathione-S-transferase P1 （GSTPI） rs1695 single nucleotide polymorphism （SNP） in 290 patients with multiple sclerosis （MS） and in 310 healthy controls. We found no significant association between the rs1695 variant and MS. Among MS patients, there was no relationship between the rs1695 variant and either gender, clinical type of MS or the age of onset of MS.

关键词： associated increased sclerosis

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Metabolic checkpoints in neurodegenerative T helper 17（TH17） and neuroregenerative regulatory T(Treg) cells as new therapeutic targets for multiple sclerosis

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Neural Regeneration Research 2020年第2期15卷 267-269页

作者： Hongxing Shen James A. Bonner Lewis Zhichang Shi Department of Radiation Oncology The University of Alabama at BirminghamBirminghamALUSA O'Neal Comprehensive Cancer Center The University of Alabama at BirminghamBirminghamALUSA Department of Microbiology The University of Alabama at BirminghamBirminghamALUSAProgram in ImmunologyThe University of Alabama at BirminghamBirminghamALUSA

The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymph... 详细信息

关键词： Metabolic checkpoints multiple sclerosis CNS

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Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis

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Neural Regeneration Research 2019年第9期14卷 1490-1493页

作者： Peter William French Russell Ian Ludowyke Gilles J.Guillemin School of Medicine University of New South WalesSydneyNSWAustralia Willoughby SydneyNSWAustralia Neuroinflammation Group Department of Biological SciencesFaculty of Medicine and Health SciencesMacquarie UniversitySydneyNSWAustralia

Fungi are important infectious disease-causing agents,but are often overlooked as environmental factors in disease.We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis(ALS),the most common form of motor neurone disease.Approximately 90%cases of ALS are sporadic,and the aetiology of sporadic ALS is still unknown.We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS.Herein we extend this proposal to water-associated fungi.A wide variety of fungi have been reported in drinking water including Acremonium,Alternaria,Aspergillus,Cladosporium,Fusarium,Penicillium and Trichoderma.Some of these are known to produce neurotoxic mycotoxins.Despite this,drinking water is not routinely monitored for fungal contamination.Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States.We propose several mechanisms by which an opportunistic fungal infection from environmental exposure(to water,soil or plants)can lead to long term neuronal degradation resulting in the hallmarks of ALS.If confirmed,the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.

关键词： amyotrophic lateral sclerosis fungi motor neurone disease mycotoxins neurotoxins ALS well water sporadic ALS

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Degenerative and regenerative processes in amyotrophic lateral sclerosis:motor reserve,adaptation and putative compensatory changes

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Neural Regeneration Research 2021年第6期16卷 1208-1209页

作者： Peter Bede Ulrich Bogdahn Jasmin Lope Kai Ming Chang Sophia Xirou Foteini Christidi Computational Neuroimaging Group Trinity College DublinDublinIreland Biomedical Imaging Laboratory Sorbonne UniversityParisFrance Department of Neurology University of RegensburgRegensburgGermany Electronics and Computer Science University of SouthamptonSouthamptonUK First Department of Neurology Aeginition HospitalNational and Kapodistrian University of AthensAthensGreece

Advances in amyotrophic lateral sclerosis(ALS)research:Research in ALS has gained unprecedented momentum in recent years fueled by important conceptual developments,establishment of international consortia,breakthrough genetic discoveries and relentless technological advances.The first genotypespecific pharmaceutical trials signal the paradigm shift from the notion of‘one-drug-for-all’to precision,individualized therapies.The once arcane presymptomatic phase of the disease is gradually unraveled by seminal studies of asymptomatic mutation carriers(Geevasinga et al.,2015;Querin et al.,2019).

关键词： al. amyotrophic sclerosis

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Multiple sclerosis:why we should focus on both sides of the(auto)antibody

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Neural Regeneration Research 2021年第12期16卷 2422-2424页

作者： Jeroen den Dunnen Lynn Mes Willianne Hoepel Joost Smolders Amsterdam Rheumatology and Immunology Center Department of Rheumatology and Clinical ImmunologyDepartment of Experimental ImmunologyAmsterdam Institute for Infection and ImmunityAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands Department of Medical Microbiology Amsterdam institute for Infection and ImmunityAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands(Mes L)Neuroimmunology Research groupNetherlands Institute for NeuroscienceAmsterdamMS Center ErasMSDepartments of Neurology and ImmunologyErasmus Medical CenterRotterdamThe Netherlands

Various clinical and experimental findings suggest a pathogenic role of antibodies in multiple sclerosis(MS).Yet,whether antibodies contribute to the pathogenesis or progression of MS is still a subject of intense debate.This controversy particularly results from unclarity regarding the target antigens of the antibodies that are found in the central nervous system(CNS)of MS patients.

关键词： sclerosis antibodies clinical

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