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1
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Lindvall O. History of cellular grafting for central nervous system repair-A clinical perspective. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:15-40. [PMID: 39341652 DOI: 10.1016/b978-0-323-90120-8.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
As late as in the 1970s, the evidence supporting that brain function might be restored by replacing dead cells by transplantation of new healthy cells was scarce in experimental animals and lacking in humans. Repairing the human brain was regarded as completely unrealistic by clinicians. Fifty years later, the situation is very different, and cellular grafting has reached patient application in several conditions affecting the CNS. The clinical studies performed so far have shown that cellular grafts can survive, grow, and function also in the diseased adult human brain. However, no proven treatment based on cell transplantation is currently available for any brain disorder. Here, the history of cellular grafting is described from a clinical perspective, including some of the preclinical work that has formed the basis for its translation to patient application. The focus is on cell transplantation for Parkinson disease, which in many ways is paving the way for this field of research. The chapter gives an account of the scientific milestones, the ups and downs, as well as the positive and negative reactions from the scientific and clinical community, and how this research field despite many obstacles has continued to move forward over more than four decades.
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Affiliation(s)
- Olle Lindvall
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden; Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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2
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Maheshwari S, Akram H, Bulstrode H, Kalia SK, Morizane A, Takahashi J, Natalwala A. Dopaminergic Cell Replacement for Parkinson's Disease: Addressing the Intracranial Delivery Hurdle. JOURNAL OF PARKINSON'S DISEASE 2024; 14:415-435. [PMID: 38457149 PMCID: PMC11091588 DOI: 10.3233/jpd-230328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 03/09/2024]
Abstract
Parkinson's disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle.
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Affiliation(s)
- Saumya Maheshwari
- The Medical School, University of Edinburgh, Edinburgh BioQuarter, UK
| | - Harith Akram
- Unit of Functional Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London, UK
| | - Harry Bulstrode
- Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Department of Clinical Neurosciences, Division of Academic Neurosurgery, University of Cambridge, Cambridge, UK
| | - Suneil K. Kalia
- Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Asuka Morizane
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Department of Regenerative Medicine, Center for Clinical Research and Innovation, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Jun Takahashi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ammar Natalwala
- Unit of Functional Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London, UK
- Department for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
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3
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Wang F, Sun Z, Peng D, Gianchandani S, Le W, Boltze J, Li S. Cell-therapy for Parkinson's disease: a systematic review and meta-analysis. J Transl Med 2023; 21:601. [PMID: 37679754 PMCID: PMC10483810 DOI: 10.1186/s12967-023-04484-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson's disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients. METHODS We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects. RESULTS The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the 'off' state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6-100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the 'off' state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis. CONCLUSIONS This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia. PROSPERO registration number: CRD42022369760.
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Affiliation(s)
- Fang Wang
- Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, China
| | - Zhengwu Sun
- Department of Clinical Pharmacy, Central Hospital of Dalian University of Technology, Dalian, China
| | - Daoyong Peng
- Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, China
| | - Shikha Gianchandani
- School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
| | - Weidong Le
- Institute of Neurology, Sichuan Academy of Medical Sciences, Sichuan Provincial Hospital, Chengdu, China
| | - Johannes Boltze
- School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
| | - Shen Li
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi Road, Beijing, 100038, China.
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.
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4
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Rájová J, Davidsson M, Avallone M, Hartnor M, Aldrin-Kirk P, Cardoso T, Nolbrant S, Mollbrink A, Storm P, Heuer A, Parmar M, Björklund T. Deconvolution of spatial sequencing provides accurate characterization of hESC-derived DA transplants in vivo. Mol Ther Methods Clin Dev 2023; 29:381-394. [PMID: 37251982 PMCID: PMC10209706 DOI: 10.1016/j.omtm.2023.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/28/2023] [Indexed: 05/31/2023]
Abstract
Cell therapy for Parkinson's disease has experienced substantial growth in the past decades with several ongoing clinical trials. Despite increasing refinement of differentiation protocols and standardization of the transplanted neural precursors, the transcriptomic analysis of cells in the transplant after its full maturation in vivo has not been thoroughly investigated. Here, we present spatial transcriptomics analysis of fully differentiated grafts in their host tissue. Unlike earlier transcriptomics analyses using single-cell technologies, we observe that cells derived from human embryonic stem cells (hESCs) in the grafts adopt mature dopaminergic signatures. We show that the presence of phenotypic dopaminergic genes, which were found to be differentially expressed in the transplants, is concentrated toward the edges of the grafts, in agreement with the immunohistochemical analyses. Deconvolution shows dopamine neurons being the dominating cell type in many features beneath the graft area. These findings further support the preferred environmental niche of TH-positive cells and confirm their dopaminergic phenotype through the presence of multiple dopaminergic markers.
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Affiliation(s)
- Jana Rájová
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Marcus Davidsson
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Martino Avallone
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Morgan Hartnor
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Patrick Aldrin-Kirk
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Tiago Cardoso
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Sara Nolbrant
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Annelie Mollbrink
- Science for Life Laboratory, Division of Gene Technology, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden
| | - Petter Storm
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Andreas Heuer
- Behavioural Neuroscience Laboratory, Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden
| | - Malin Parmar
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Tomas Björklund
- Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
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5
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Savitz SI, Cox CS. Cell-based therapies for neurological disorders - the bioreactor hypothesis. Nat Rev Neurol 2023; 19:9-18. [PMID: 36396913 DOI: 10.1038/s41582-022-00736-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2022] [Indexed: 11/18/2022]
Abstract
Cell-based therapies are an emerging biopharmaceutical paradigm under investigation for the treatment of a range of neurological disorders. Accumulating evidence is demonstrating that cell-based therapies might be effective, but the mechanism of action remains unclear. In this Review, we synthesize results from over 20 years of animal studies that illustrate how transdifferentiation, cell replacement and restoration of damaged tissues in the CNS are highly unlikely mechanisms. We consider the evidence for an alternative model that we refer to as the bioreactor hypothesis, in which exogenous cells migrate to peripheral organs and modulate and reprogramme host immune cells to generate an anti-inflammatory, regenerative environment. The results of clinical trials clearly demonstrate a role for immunomodulation in the effects of cell-based therapies. Greater understanding of these mechanisms could facilitate the optimization of cell-based therapies for a variety of neurological disorders.
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Affiliation(s)
- Sean I Savitz
- Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston, TX, USA. .,Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
| | - Charles S Cox
- Department of Pediatric Surgery, University of Texas Health Science Center, Houston, TX, USA
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6
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Salahi S, Mousavi MA, Azizi G, Hossein-Khannazer N, Vosough M. Stem Cell-based and Advanced Therapeutic Modalities for Parkinson's Disease: A Risk-effectiveness Patient-centered Analysis. Curr Neuropharmacol 2022; 20:2320-2345. [PMID: 35105291 PMCID: PMC9890289 DOI: 10.2174/1570159x20666220201100238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/14/2022] [Accepted: 01/26/2022] [Indexed: 12/29/2022] Open
Abstract
Treatment of Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is currently considered a challenging issue since it causes substantial disability, poor quality of life, and mortality. Despite remarkable progress in advanced conventional therapeutic interventions, the global burden of the disease has nearly doubled, prompting us to assess the riskeffectiveness of different treatment modalities. Each protocol could be considered as the best alternative treatment depending on the patient's situation. Prescription of levodopa, the most effective available medicine for this disorder, has been associated with many complications, i.e., multiple episodes of "off-time" and treatment resistance. Other medications, which are typically used in combination with levodopa, may have several adverse effects as well. As a result, the therapies that are more in line with human physiology and make the least interference with other pathways are worth investigating. On the other hand, remaining and persistent symptoms after therapy and the lack of effective response to the conventional approaches have raised expectations towards innovative alternative approaches, such as stem cell-based therapy. It is critical to not overlook the unexplored side effects of innovative approaches due to the limited number of research. In this review, we aimed to compare the efficacy and risk of advanced therapies with innovative cell-based and stemcell- based modalities in PD patients. This paper recapitulated the underlying factors/conditions, which could lead us to more practical and established therapeutic outcomes with more advantages and few complications. It could be an initial step to reconsider the therapeutic blueprint for patients with Parkinson's disease.
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Affiliation(s)
- Sarvenaz Salahi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Alsadat Mousavi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research, Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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7
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Lane EL, Lelos MJ. Defining the unknowns for cell therapies in Parkinson's disease. Dis Model Mech 2022; 15:dmm049543. [PMID: 36165848 PMCID: PMC9555765 DOI: 10.1242/dmm.049543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.
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Affiliation(s)
- Emma L. Lane
- Cardiff School of Pharmacy and Pharmaceutical Sciences, King Edward VII Avenue, Cardiff University, Cardiff CF10 3NB, UK
| | - Mariah J. Lelos
- School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF10 3AX, UK
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8
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Lendahl U. 100 plus years of stem cell research-20 years of ISSCR. Stem Cell Reports 2022; 17:1248-1267. [PMID: 35705014 PMCID: PMC9213821 DOI: 10.1016/j.stemcr.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/25/2022] [Accepted: 04/05/2022] [Indexed: 11/25/2022] Open
Abstract
The International Society for Stem Cell Research (ISSCR) celebrates its 20th anniversary in 2022. This review looks back at some of the key developments in stem cell research as well as the evolution of the ISSCR as part of that field. Important discoveries from stem cell research are described, and how the improved understanding of basic stem cell biology translates into new clinical therapies and insights into disease mechanisms is discussed. Finally, the birth and growth of ISSCR into a leading stem cell society and a respected voice for ethics, advocacy, education and policy in stem cell research are described.
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Affiliation(s)
- Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
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9
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Li JY, Li W. Postmortem Studies of Fetal Grafts in Parkinson's Disease: What Lessons Have We Learned? Front Cell Dev Biol 2021; 9:666675. [PMID: 34055800 PMCID: PMC8155361 DOI: 10.3389/fcell.2021.666675] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/06/2021] [Indexed: 12/28/2022] Open
Abstract
Neural transplantation is a potential therapeutic method for Parkinson’s disease (PD). Fetal dopaminergic (DA) neurons have been important transplantation cell sources in the history of replacement therapy for PD. Several decades of preclinical animal experiments and clinical trials using fetal DA neuron transplantation in PD therapy have shown not only promising results but also problems. In order to reveal possible factors influencing the clinical outcomes, we reviewed fetal DA neuron transplantation therapies from 1970s to present, with a special focus on postmortem studies. Firstly, we gave a general description of the clinical outcomes and neuroanatomy of grafted cases; secondly, we summarized the main available postmortem studies, including the cell survival, reinnervation, and pathology development. In the end, we further discussed the link between function and structure of the grafts, seeking for the possible factors contributing to a functional graft. With our review, we hope to provide references for future transplantation trials from a histological point of view.
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Affiliation(s)
- Jia-Yi Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Wen Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
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10
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Katolikova NV, Malashicheva AB, Gainetdinov RR. Cell Replacement Therapy in Parkinson’s Disease—History of Development and Prospects for Use in Clinical Practice. Mol Biol 2021. [DOI: 10.1134/s0026893320060060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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11
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Salado-Manzano C, Perpiña U, Straccia M, Molina-Ruiz FJ, Cozzi E, Rosser AE, Canals JM. Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases? Front Cell Neurosci 2020; 14:250. [PMID: 32848630 PMCID: PMC7433375 DOI: 10.3389/fncel.2020.00250] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.
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Affiliation(s)
- Cristina Salado-Manzano
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Unai Perpiña
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | | | - Francisco J. Molina-Ruiz
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Emanuele Cozzi
- Department of Cardio-Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
- Transplant Immunology Unit, Padua University Hospital, Padua, Italy
| | - Anne E. Rosser
- Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Josep M. Canals
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Networked Biomedical Research Centre for Neurodegenerative Disorders (CIBERNED), Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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12
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Kim TW, Koo SY, Studer L. Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities. Front Cell Dev Biol 2020; 8:729. [PMID: 32903681 PMCID: PMC7438741 DOI: 10.3389/fcell.2020.00729] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/15/2020] [Indexed: 12/16/2022] Open
Abstract
In Parkinson's disease (PD), there are currently no effective therapies to prevent or slow down disease progression. Cell replacement therapy using human pluripotent stem cell (hPSC)-derived dopamine neurons holds considerable promise. It presents a novel, regenerative strategy, building on the extensive history of fetal tissue grafts and capturing the potential of hPSCs to serve as a scalable and standardized cell source. Progress in establishing protocols for the direct differentiation to midbrain dopamine (mDA) neurons from hPSC have catalyzed the development of cell-based therapies for PD. Consequently, several groups have derived clinical-grade mDA neuron precursors under clinical good manufacture practice condition, which are progressing toward clinical testing in PD patients. Here we will review the current status of the field, discuss the remaining key challenges, and highlight future areas for further improvements of hPSC-based technologies in the clinical translation to PD.
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Affiliation(s)
- Tae Wan Kim
- The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States.,Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States
| | - So Yeon Koo
- The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States.,Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States.,Neuroscience Graduate Program of Weill Cornell Graduate School of Biomedical Sciences, Weill Cornell Medicine, New York, NY, United States
| | - Lorenz Studer
- The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States.,Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States
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13
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Henchcliffe C, Sarva H. Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson's Disease. CNS Drugs 2020; 34:559-577. [PMID: 32472450 DOI: 10.1007/s40263-020-00727-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
There is escalating interest in cell-based therapies to restore lost dopamine inputs in Parkinson's disease. This is based upon the rationale that implanting dopamine progenitors into the striatum can potentially improve dopamine-responsive motor symptoms. A rich body of data describing clinical trials of previous cell transplantation exists. These have included multiple cell sources for transplantation including allogeneic (human embryonic mesencephalic tissue, retinal pigment epithelial cells) and autologous (carotid body, adrenal medullary tissue) cells, as well as xenotransplantation. However, there are multiple limitations related to these cell sources, including availability of adequate numbers of cells for transplant, heterogeneity within cells transplanted, imprecisely defined mechanisms of action, and poor cell survival after transplantation in some cases. Nonetheless, evidence has accrued from a subset of trials to support the rationale for such a regenerative approach. Recent rapid advances in stem cell technology may now overcome these prior limitations. For example, dopamine neuron precursor cells for transplant can be generated from induced pluripotent cells and human embryonic stem cells. The benefits of these innovative approaches include: the possibility of scalability; a high degree of quality control; and improved understanding of mechanisms of action with rigorous preclinical testing. In this review, we focus on the potential for cell-based therapies in Parkinson's disease to restore the function of dopaminergic neurons, we critically review previous attempts to harness such strategies, we discuss potential benefits and predicted limitations, and we address how previous roadblocks may be overcome to bring a cell-based approach to the clinic.
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Affiliation(s)
- Claire Henchcliffe
- Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA.
| | - Harini Sarva
- Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA
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14
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Schweitzer JS, Song B, Leblanc PR, Feitosa M, Carter BS, Kim KS. Columnar Injection for Intracerebral Cell Therapy. Oper Neurosurg (Hagerstown) 2020; 18:321-328. [PMID: 31214702 PMCID: PMC7311830 DOI: 10.1093/ons/opz143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 02/15/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Surgical implantation of cellular grafts into the brain is of increasing importance, as stem cell-based therapies for Parkinson and other diseases continue to develop. The effect of grafting technique on development and survival of the graft has received less attention. Rate and method of graft delivery may impact the cell viability and success of these therapies. Understanding the final location of the graft with respect to the intended target location is also critical. OBJECTIVE To describe a "columnar injection" technique designed to reduce damage to host tissue and result in a column of graft material with greater surface area to volume ratio than traditional injection techniques. METHODS Using a clinically relevant model system of human embryonic stem cell-derived dopaminergic progenitors injected into athymic rat host brain, we describe a novel device that allows separate control of syringe barrel and plunger, permitting precise deposition of the contents into the cannula tract during withdrawal. Controls consist of contralateral injection using traditional techniques. Graft histology was examined at graft maturity. RESULTS Bolus grafts were centered on the injection tract but were largely proximal to the "target" location. These grafts displayed a conspicuous peripheral distribution of cells, particularly of mature dopaminergic neurons. In contrast, column injections remained centered at the intended target, contained more evenly distributed cells, and had significantly more mature dopaminergic neurons. CONCLUSION We suggest that this columnar injection technique may allow better engraftment and development of intracerebral grafts, enhancing outcomes of cell therapy, compared to fixed-point injection techniques.
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Affiliation(s)
- Jeffrey S Schweitzer
- Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts
- Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts
| | - Bin Song
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
- Molecular Neurobiology Laboratory, Program in Neuroscience, and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
| | - Pierre R Leblanc
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
- Molecular Neurobiology Laboratory, Program in Neuroscience, and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
| | - Melissa Feitosa
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
- Molecular Neurobiology Laboratory, Program in Neuroscience, and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts
- Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts
| | - Kwang-Soo Kim
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
- Molecular Neurobiology Laboratory, Program in Neuroscience, and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
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15
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Jamebozorgi K, Taghizadeh E, Rostami D, Pormasoumi H, Barreto GE, Hayat SMG, Sahebkar A. Cellular and Molecular Aspects of Parkinson Treatment: Future Therapeutic Perspectives. Mol Neurobiol 2019; 56:4799-4811. [PMID: 30397850 DOI: 10.1007/s12035-018-1419-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/29/2018] [Indexed: 12/12/2022]
Abstract
Parkinson's disease is a neurodegenerative disorder accompanied by depletion of dopamine and loss of dopaminergic neurons in the brain that is believed to be responsible for the motor and non-motor symptoms in this disease. The main drug prescribed for Parkinsonian patients is L-dopa, which can be converted to dopamine by passing through the blood-brain barrier. Although L-dopa is able to improve motor function and improve the quality of life in the patients, there is inter-individual variability and some patients do not achieve the therapeutic effect. Variations in treatment response and side effects of current drugs have convinced scientists to think of treating Parkinson's disease at the cellular and molecular level. Molecular and cellular therapy for Parkinson's disease include (i) cell transplantation therapy with human embryonic stem (ES) cells, human induced pluripotent stem (iPS) cells and human fetal mesencephalic tissue, (ii) immunological and inflammatory therapy which is done using antibodies, and (iii) gene therapy with AADC-TH-GCH gene therapy, viral vector-mediated gene delivery, RNA interference-based therapy, CRISPR-Cas9 gene editing system, and alternative methods such as optogenetics and chemogenetics. Although these methods currently have a series of challenges, they seem to be promising techniques for Parkinson's treatment in future. In this study, these prospective therapeutic approaches are reviewed.
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Affiliation(s)
| | - Eskandar Taghizadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Departments of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Daryoush Rostami
- Department of School Allied, Zabol University of Medical Sciences, Zabol, Iran
| | - Hosein Pormasoumi
- Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | | | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box: 91779-48564, Mashhad, Iran.
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16
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Trabecular meshwork mesenchymal stem cell transplantation improve motor symptoms of parkinsonian rat model. Biologicals 2019; 61:61-67. [PMID: 31262640 DOI: 10.1016/j.biologicals.2019.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 03/21/2019] [Accepted: 06/26/2019] [Indexed: 01/26/2023] Open
Abstract
Stem cell transplantation is a new therapeutic strategy in the treatment of neurodegenerative disorders such as Parkinson's disease (PD). Therefore, in this study, the therapeutic effects of Trabecular Meshwork Mesenchymal Stem Cells (TM-MSCs) transplantation, as a new source of mesenchymal stem cells, were evaluated in the animal model of PD. After the development and confirmation of hemi-parkinsonian rats by administration of 6-hydroxy dopamine (6-OHDA) and apomorphine-induced rotation test, green fluorescent protein (GFP) labeled TM-MSCs (normal and induced cells) were transplanted in the striatum of rats. Next, the rotation test, rotarod test, open field, passive avoidance memory tests and immunohistochemistry for tyrosine hydroxylase (TH) were done. The results showed that the number of turns significantly decreased and the improvement of motor performance was achieved after cell transplantation. However, there was no significant difference in passive avoidance memory of animals documented by shuttle box test. The number of GFP- labeled cells expressing TH significantly is increased compared to the vehicle group. Collectively, it seems that TM-MSCs and induced TM-MSCs cell transplantation have positive effects on some aspects of the animal model of PD. Other studies may reveal the potentially positive aspects of these cells in the laboratory and clinical studies.
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17
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Abstract
Parkinson's disease is the second most common neurodegenerative disorder. It is characterised by a typical movement disorder that occurs in part because of the selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Current treatment for the motor disorder of Parkinson's disease consists of dopaminergic medications, but these come with significant adverse effects, themselves an important part of the clinical course of Parkinson's disease, particularly in advanced stages. Therefore, treatment is needed that can restore dopaminergic tone in the striatum in a physiological and targeted manner to avert these side effects. A number of potential regenerative treatments have been developed with a view to achieving this. Following decades of optimisation and development of stem-cell-based treatments and viral gene delivery, clinical trials are on the horizon. For these treatments to be widely useful, they must be clinically effective, cost efficient and safe, and a number of practical aspects regarding storage and delivery of treatment must be optimised. Many barriers have been overcome, and the field of regenerative medicine for Parkinson's disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches.
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18
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Stoker TB, Torsney KM, Barker RA. Emerging Treatment Approaches for Parkinson's Disease. Front Neurosci 2018; 12:693. [PMID: 30349448 PMCID: PMC6186796 DOI: 10.3389/fnins.2018.00693] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 09/18/2018] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease, manifesting as a characteristic movement disorder with a number of additional non-motor features. The pathological hallmark of PD is the presence of intra-neuronal aggregates of α-synuclein (Lewy bodies). The movement disorder of PD occurs largely due to loss of dopaminergic neurons of the substantia nigra, resulting in striatal dopamine depletion. There are currently no proven disease modifying treatments for PD, with management options consisting mainly of dopaminergic drugs, and in a limited number of patients, deep brain stimulation. Long-term use of established dopaminergic therapies for PD results in significant adverse effects, and there is therefore a requirement to develop better means of restoring striatal dopamine, as well as treatments that are able to slow progression of the disease. A number of exciting treatments have yielded promising results in pre-clinical and early clinical trials, and it now seems likely that the landscape for the management of PD will change dramatically in the short to medium term future. Here, we discuss the promising regenerative cell-based and gene therapies, designed to treat the dopaminergic aspects of PD whilst limiting adverse effects, as well as novel approaches to reducing α-synuclein pathology.
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Affiliation(s)
- Thomas B Stoker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.,Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Kelli M Torsney
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.,Department of Medicine for the Elderly, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Roger A Barker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.,Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
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19
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Lane EL. L-DOPA for Parkinson's disease-a bittersweet pill. Eur J Neurosci 2018; 49:384-398. [PMID: 30118169 DOI: 10.1111/ejn.14119] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/23/2018] [Accepted: 07/30/2018] [Indexed: 01/02/2023]
Abstract
3,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long-term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L-DOPA-induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L-DOPA. However, L-DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L-DOPA with a focus on its potential impact on advanced reparative interventions.
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Affiliation(s)
- Emma L Lane
- Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
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20
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Kumar S, Yadav N, Pandey S, Thelma BK. Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects. J Genet 2018. [DOI: 10.1007/s12041-018-0953-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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21
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Padmanabhan S, Burke RE. Induction of axon growth in the adult brain: A new approach to restoration in Parkinson's disease. Mov Disord 2017; 33:62-70. [PMID: 29205486 DOI: 10.1002/mds.27209] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 09/27/2017] [Accepted: 10/02/2017] [Indexed: 12/19/2022] Open
Affiliation(s)
| | - Robert E Burke
- Department of Neurology, Columbia University, New York, New York, USA.,Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
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22
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Grade S, Götz M. Neuronal replacement therapy: previous achievements and challenges ahead. NPJ Regen Med 2017; 2:29. [PMID: 29302363 PMCID: PMC5677983 DOI: 10.1038/s41536-017-0033-0] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 09/22/2017] [Accepted: 09/25/2017] [Indexed: 12/26/2022] Open
Abstract
Lifelong neurogenesis and incorporation of newborn neurons into mature neuronal circuits operates in specialized niches of the mammalian brain and serves as role model for neuronal replacement strategies. However, to which extent can the remaining brain parenchyma, which never incorporates new neurons during the adulthood, be as plastic and readily accommodate neurons in networks that suffered neuronal loss due to injury or neurological disease? Which microenvironment is permissive for neuronal replacement and synaptic integration and which cells perform best? Can lost function be restored and how adequate is the participation in the pre-existing circuitry? Could aberrant connections cause malfunction especially in networks dominated by excitatory neurons, such as the cerebral cortex? These questions show how important connectivity and circuitry aspects are for regenerative medicine, which is the focus of this review. We will discuss the impressive advances in neuronal replacement strategies and success from exogenous as well as endogenous cell sources. Both have seen key novel technologies, like the groundbreaking discovery of induced pluripotent stem cells and direct neuronal reprogramming, offering alternatives to the transplantation of fetal neurons, and both herald great expectations. For these to become reality, neuronal circuitry analysis is key now. As our understanding of neuronal circuits increases, neuronal replacement therapy should fulfill those prerequisites in network structure and function, in brain-wide input and output. Now is the time to incorporate neural circuitry research into regenerative medicine if we ever want to truly repair brain injury.
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Affiliation(s)
- Sofia Grade
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians University Munich, 82152 Planegg-Martinsried, Germany
- Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Magdalena Götz
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians University Munich, 82152 Planegg-Martinsried, Germany
- Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- SYNERGY, Excellence Cluster of Systems Neurology, Biomedical Center, Ludwig-Maximilians University Munich, 82152 Planegg-Martinsried, Germany
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23
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Torres N, Molet J, Moro C, Mitrofanis J, Benabid AL. Neuroprotective Surgical Strategies in Parkinson's Disease: Role of Preclinical Data. Int J Mol Sci 2017; 18:ijms18102190. [PMID: 29053638 PMCID: PMC5666871 DOI: 10.3390/ijms18102190] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 12/18/2022] Open
Abstract
Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson's disease (PD) patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI) using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF) administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials.
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Affiliation(s)
- Napoleon Torres
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - Jenny Molet
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - Cecile Moro
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - John Mitrofanis
- Department of Anatomy, University of Sydney; Sydney Medical School, Sydney NSW 2006, Australia.
| | - Alim Louis Benabid
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
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24
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Li S, Le W. Milestones of Parkinson's Disease Research: 200 Years of History and Beyond. Neurosci Bull 2017; 33:598-602. [PMID: 28895075 DOI: 10.1007/s12264-017-0178-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 08/04/2017] [Indexed: 11/26/2022] Open
Affiliation(s)
- Song Li
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China
- Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China
| | - Weidong Le
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China.
- Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
- Collaborative Innovation Center for Brain Science, The First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
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25
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Gómez-Paz A, Drucker-Colín R, Milán-Aldaco D, Palomero-Rivero M, Ambriz-Tututi M. Intrastriatal Chromospheres' Transplant Reduces Nociception in Hemiparkinsonian Rats. Neuroscience 2017; 387:123-134. [PMID: 28890053 DOI: 10.1016/j.neuroscience.2017.08.052] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 08/20/2017] [Accepted: 08/29/2017] [Indexed: 10/18/2022]
Abstract
The present study evaluates the possible antinociceptive effect of chromosphere transplants in rats injected with 6-hydroxydopamine (6-OHDA), a model of Parkinson's disease. Male adult Wistar rats received 40μg/0.5μl of 6-OHDA or 0.5μl of vehicle into the left substantia nigra (SNc). Rats were evaluated for mechanical allodynia, cold allodynia, thermal hyperalgesia and formalin. Rats with altered nociceptive threshold were transplanted with chromospheres. After transplant, rats were evaluated every week. Our results confirm that 6-OHDA injection into rat's SNc reduces mechanical, thermal, and chemical thresholds. Interestingly, chromospheres' transplant reverted 6-OHDA-induced allodynia and hyperalgesia. The antinociceptive effect induced by chromospheres was dopamine D2- and opioid-receptor dependent since sulpiride or naltrexone reverted its effect.
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Affiliation(s)
- Alejandra Gómez-Paz
- Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
| | - René Drucker-Colín
- Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
| | - Diana Milán-Aldaco
- Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
| | - Marcela Palomero-Rivero
- Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
| | - Mónica Ambriz-Tututi
- Hospital General Ajusco Medio "Dra. Obdulia Rodriguez Rodriguez", Unidad de, Trastornos de Movimiento y Sueño, Mexico.
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26
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Sun AX, Tan EK. Towards better cellular replacement therapies in Parkinson disease. J Neurosci Res 2017; 96:219-221. [PMID: 28791710 DOI: 10.1002/jnr.24123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/04/2017] [Accepted: 07/05/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Alfred Xuyang Sun
- National Neuroscience Institute, Singapore General Hospital, Duke NUS Medical School, Genome Institute of Singapore, Singapore
| | - Eng-King Tan
- National Neuroscience Institute, Singapore General Hospital, Duke NUS Medical School, Genome Institute of Singapore, Singapore
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27
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Schueler SB, Sagen J, Pappas GD, Kordower JH. Long-Term Viability of Isolated Bovine Adrenal Medullary Chromaffin Cells following Intrastriatal Transplantation. Cell Transplant 2017; 4:55-64. [PMID: 7728334 DOI: 10.1177/096368979500400109] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Adrenal medullary grafts generally exhibit poor viability when grafted into the striatum. Previous work in our laboratory demonstrated that chromaffin cells can survive well for up to 2 mo following grafting into the intact rat striatum after cells are isolated from the nonchromaffin supporting cells (fibroblasts and endothelial cells) of the adrenal medulla. The aim of the present study was to assess the long-term viability of isolated bovine chromaffin cells following grafting into the intact rat striatum. The viability of grafted bovine adrenal medullary chromaffin cells was compared in rats receiving either (a) perfused adrenal medulla; (b) isolated chromaffin cells; or (c) isolated chromaffin cells that were subsequently recombined with their nonchromaffin supporting cells. One year postimplantation, all graft types which included fibroblasts and endothelial cells were infiltrated with macrophages and demonstrated an abundance of cellular debris. No viable chromaffin cells were observed. In contrast, healthy tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DβH) immunoreactive chromaffin cells survived for 1 yr posttransplantation when grafted in isolation from the nonchromaffin constituents of the adrenal medulla. Good xenograft survival was achieved in this group despite the fact that these rats were only immunosuppressed for 1 mo postimplantation. Grafted cells demonstrated morphological characteristics of chromaffin cells in situ and these implants were not accompanied by macrophage infiltration. These data demonstrate that long-term survival of chromaffin cells can be achieved following intrastriatal implantation and the viability of grafted chromaffin cells is dependent upon the removal of the nonchromaffin supporting cells.
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Affiliation(s)
- S B Schueler
- Department of Anatomy and Cell Biology, University of Illinois School of Medicine, Chicago 60612, USA
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28
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Boronat-García A, Guerra-Crespo M, Drucker-Colín R. Historical perspective of cell transplantation in Parkinson’s disease. World J Transplant 2017; 7:179-192. [PMID: 28698835 PMCID: PMC5487308 DOI: 10.5500/wjt.v7.i3.179] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 04/27/2017] [Accepted: 05/15/2017] [Indexed: 02/05/2023] Open
Abstract
Cell grafting has been considered a therapeutic approach for Parkinson’s disease (PD) since the 1980s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of cell-transplantation for PD consists in grafting dopamine-producing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.
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29
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Emerich DF, Ragozzino M, Lehman MN, Sanberg PR. Behavioral Effects of Neural Transplantation. Cell Transplant 2017; 1:401-27. [PMID: 1344313 DOI: 10.1177/096368979200100604] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Considerable evidence suggests that transplantation of fetal neural tissue ameliorates the behavioral deficits observed in a variety of animal models of CNS disorders. However, it is also becoming increasingly clear that neural transplants do not necessarily produce behavioral recovery, and in some cases have either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Regardless, studies demonstrating the successful use of neural transplants in reducing or eliminating behavioral deficits in these animal models has led directly to their clinical application in human neurodegenerative disorders such as Parkinson's disease. This review examines the beneficial and deleterious behavioral consequences of neural transplants in different animal models of human diseases, and discusses the possible mechanisms by which neural transplants might produce behavior recovery.
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Affiliation(s)
- D F Emerich
- Cyto Therapeutics, Inc., Providence, RI 02906
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30
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Hara K, Uchida K, Fukunaga A, Toya S, Kawase T. Implantation of Xenogeneic Transgenic Neural Plate Tissues into Parkinsonian Rat Brain. Cell Transplant 2017; 6:515-9. [PMID: 9331504 DOI: 10.1177/096368979700600513] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Xenografting must be considered as a means of establishing neural transplantation therapy and of securing fetal neural tissues as donor material. The early stage (embryonic day 8.5, E8.5) embryonic mesencephalic neural plate (NP) from transgenic mice was examined for possible application in effective xenografting therapy. As recipients, Parkinsonian rats treated with 6-hydroxydopamine were used, and as donors, GT4-2 mice into which a β-galactosidase gene was introduced to allow brain tissue differentiation from the recipients by X-gal staining. Three microscopic pieces of E8.5 GT4-2 mice NP were injected into the striatum of the Parkinsonian rats. Some hosts were given immunosuppressants (cyclophosphamide and FK506) (IS group), others were not (non-IS group). Amphetamine-induced rotation was examined at days 11 and 21 after grafting (D11 and D21, respectively), and morphological investigations were performed using hematoxylin-eosin (H-E), X-gal, and thyrosine hydroxylase (TH) staining. The rotations were counted in 30 of the 38 transplanted rats before and after grafting. Histological data were obtained from 19 of these 30 rats. In 11 of them the grafts survived (survival group) and in the remaining 8, the grafts were unsuccessful (rejection group). In the survival group at D11, the mean number of rotations made by transplanted rats expressed as a percentage of the number before grafting (rotation percentage) decreased to 43.8% (n = 9), which, in comparison with the average of 125.9% (n = 6) in the rejection group, reveals significant behavioral recovery (p < 0.01). The rotation percentage at D21 was 23.8% in the survival group (n = 4) and 84.5% in the rejection group (n = 3). Behavioral recovery was thus seen to improve with time in the survival group. In the IS group (n = 19), the rotation percentages averaged 74.9% (D11, n = 15) and 51.1% (D21, n = 7), while the non-IS group averages were 136.7% (D11, n = 9) and 140.7% (D21, n = 9), indicating a tendency for better behavioral recovery in the IS group than in the non-IS group (p < 0.05). Fifteen IS group rats were studied histologically, 10 (sacrificed on D11, D21) from the survival group and 5 (sacrificed on D11, D21) from the rejection group. In the non-IS group (n = 4), there was a graft in only one rat sacrificed on D11. There were many X-gal positive and TH positive cells in the grafts, suggesting that mouse NP survived, and differentiated into TH positive neurons in the rat brain. Xenografted NP has the potential to cure central nervous system diseases.
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Affiliation(s)
- K Hara
- Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan
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Non-human primate models of PD to test novel therapies. J Neural Transm (Vienna) 2017; 125:291-324. [PMID: 28391443 DOI: 10.1007/s00702-017-1722-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 04/04/2017] [Indexed: 12/13/2022]
Abstract
Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson. However, involuntary movements termed L-Dopa-induced dyskinesias appear in most patients after chronic treatment and may become disabling. Dyskinesias are very difficult to manage and there is only amantadine approved providing only a modest benefit. In this respect, NHP models have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients. Therapies to treat motor symptoms in NHP models are reviewed with a discussion of their translational value to humans. Disease-modifying treatments tested in NHP are reviewed as well as surgical treatments. Many biochemical changes in the brain of post-mortem Parkinson disease patients with dyskinesias are reviewed and compare well with those observed in NHP models. Non-motor symptoms can be categorized into psychiatric, autonomic, and sensory symptoms. These symptoms are present in most parkinsonian patients and are already installed many years before the pre-motor phase of the disease. The translational usefulness of NHP models of Parkinson is discussed for non-motor symptoms.
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Vermilyea SC, Emborg ME. The role of nonhuman primate models in the development of cell-based therapies for Parkinson's disease. J Neural Transm (Vienna) 2017; 125:365-384. [PMID: 28326445 PMCID: PMC5847191 DOI: 10.1007/s00702-017-1708-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 03/12/2017] [Indexed: 12/23/2022]
Abstract
Through the course of over three decades, nonhuman primate (NHP) studies on cell-based therapies (CBTs) for Parkinson’s disease (PD) have provided insight into the feasibility, safety and efficacy of the approach, methods of cell collection and preparation, cell viability, as well as potential brain targets. Today, NHP research continues to be a vital source of information for improving cell grafts and analyzing how the host affects graft survival, integration and function. Overall, this article aims to discuss the role that NHP models of PD have played in CBT development and highlights specific issues that need to be considered to maximize the value of NHP studies for the successful clinical translation of CBTs.
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Affiliation(s)
- Scott C Vermilyea
- Neuroscience Training Program, University of Wisconsin, Madison, 1220 Capitol Court, Madison, WI, 53715, USA.,Wisconsin National Primate Research Center, University of Wisconsin, Madison, USA
| | - Marina E Emborg
- Neuroscience Training Program, University of Wisconsin, Madison, 1220 Capitol Court, Madison, WI, 53715, USA. .,Wisconsin National Primate Research Center, University of Wisconsin, Madison, USA. .,Department of Medical Physics, University of Wisconsin, Madison, USA.
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Takahashi H, Ishikawa H, Tanaka A. Regenerative medicine for Parkinson's disease using differentiated nerve cells derived from human buccal fat pad stem cells. Hum Cell 2017; 30:60-71. [PMID: 28210976 DOI: 10.1007/s13577-017-0160-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/16/2017] [Indexed: 01/29/2023]
Abstract
The purpose of this study was to evaluate the utility of human adipose stem cells derived from the buccal fat pad (hBFP-ASCs) for nerve regeneration. Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons. PD is a candidate disease for cell replacement therapy because it has no fundamental therapeutic methods. We examined the properties of neural-related cells induced from hBFP-ASCs as a cell source for PD treatment. hBFP-ASCs were cultured in neurogenic differentiation medium for about 2 weeks. After the morphology of hBFP-ASCs changed to neural-like cells, the medium was replaced with neural maintenance medium. Cells differentiated from hBFP-ASCs showed neuron-like structures and expressed neuron markers (β3-tubulin, neurofilament 200, and microtubule-associated protein 2), an astrocyte marker (glial fibrillary acidic protein), or dopaminergic neuron-related marker (tyrosine hydroxylase). Induced neural cells were transplanted into a 6-hydroxydopamine (6-OHDA)-lesioned rat hemi-parkinsonian model. At 4 weeks after transplantation, 6-OHDA-lesioned rats were subjected to apomorphine-induced rotation analysis. The transplanted cells survived in the brain of rats as dopaminergic neural cells. No tumor formation was found after cell transplantation. We demonstrated differentiation of hBFP-ASCs into neural cells, and that transplantation of these neural cells improved the symptoms of model rats. Our results suggest that neurons differentiated from hBFP-ASCs would be applicable to cell replacement therapy of PD.
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Affiliation(s)
- Haruka Takahashi
- Oral and Maxillofacial Surgery, Field of Oral and Maxillofacial Surgery and Systemic Medicine, Course of Clinical Science, Nippon Dental University Graduate School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan.
| | - Hiroshi Ishikawa
- Department of NDU Life Sciences, Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Akira Tanaka
- Department of Oral and Maxillofacial Surgery, Nippon Dental University School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan
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Björklund A, Lindvall O. Replacing Dopamine Neurons in Parkinson's Disease: How did it happen? JOURNAL OF PARKINSON'S DISEASE 2017; 7:S21-S31. [PMID: 28282811 PMCID: PMC5345652 DOI: 10.3233/jpd-179002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.
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Affiliation(s)
- Anders Björklund
- Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden
| | - Olle Lindvall
- Department of Clinical Sciences, and Lund Stem Cell Center, Division of Neurology, University Hospital, Lund, Sweden
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Abstract
Over the past three decades, significant progress has been made in the development of potential regenerative cell-based therapies for neurodegenerative disease, with most success being seen in Parkinson's disease. Cell-based therapies face many challenges including ethical considerations, potential for immune-mediated rejection with allogeneic and xenogeneic tissue, pathological spread of protein-related disease into the grafted tissue as well as the risk of graft overgrowth and tumorigenesis in stem cell-derived transplants. Preclinical trials have looked at many tissue types of which the most successful to date have been those using fetal ventral mesencephalon grafts, which led to clinical trials, which have shown that in some cases they can work very well. With important proof-of-concept derived from these studies, there is now much interest in how dopaminergic neurons derived from stem cell sources could be used to develop cell-based therapies suitable for clinical use, with clinical trials poised to enter the clinic in the next couple of years.
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Affiliation(s)
- Thomas B Stoker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, CB2 0PY, UK.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge
| | - Roger A Barker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, CB2 0PY, UK.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge
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Pramanik S, Sulistio YA, Heese K. Neurotrophin Signaling and Stem Cells-Implications for Neurodegenerative Diseases and Stem Cell Therapy. Mol Neurobiol 2016; 54:7401-7459. [PMID: 27815842 DOI: 10.1007/s12035-016-0214-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 10/11/2016] [Indexed: 02/07/2023]
Abstract
Neurotrophins (NTs) are members of a neuronal growth factor protein family whose action is mediated by the tropomyosin receptor kinase (TRK) receptor family receptors and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor family. Although NTs were first discovered in neurons, recent studies have suggested that NTs and their receptors are expressed in various types of stem cells mediating pivotal signaling events in stem cell biology. The concept of stem cell therapy has already attracted much attention as a potential strategy for the treatment of neurodegenerative diseases (NDs). Strikingly, NTs, proNTs, and their receptors are gaining interest as key regulators of stem cells differentiation, survival, self-renewal, plasticity, and migration. In this review, we elaborate the recent progress in understanding of NTs and their action on various stem cells. First, we provide current knowledge of NTs, proNTs, and their receptor isoforms and signaling pathways. Subsequently, we describe recent advances in the understanding of NT activities in various stem cells and their role in NDs, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Finally, we compile the implications of NTs and stem cells from a clinical perspective and discuss the challenges with regard to transplantation therapy for treatment of AD and PD.
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Affiliation(s)
- Subrata Pramanik
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea
| | - Yanuar Alan Sulistio
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
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Corey S, Lippert T, Borlongan CV. Translational lab-to-clinic hurdles in stem cell therapy. Chin Neurosurg J 2016. [DOI: 10.1186/s41016-016-0058-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Devi MG, Sharma A, Mohanty S, Jain N, Verma K, Padma MV, Pal P, Chabbra HS, Khadilkar S, Prabhakar S, Singh G. Report: Stem cell applications in neurological practice, an expert group consensus appraisal. Ann Indian Acad Neurol 2016; 19:367-73. [PMID: 27570390 PMCID: PMC4980961 DOI: 10.4103/0972-2327.186825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Introduction: Neurologists in their clinical practice are faced with inquiries about the suitability of stem cell approaches by patients with a variety of acute and chronic (namely neurodegenerative) disorders. The challenge is to provide these patients with accurate information about the scope of stem cell use as well as at the same time, empowering patients with the capacity to make an autonomous decision regarding the use of stem cells. Methods: The Indian Academy of Neurology commissioned an Expert Group Meeting to formulate an advisory to practicing neurologists to counsel patients seeking information and advice about stem cell approaches. Results and Conclusions: In the course of such counselling, it should be emphasized that the information provided by many lay websites might be unsubstantiated. Besides, standard recommendations for the stem cell research, in particular, the application of several layers of oversight should be strictly adhered in order to ensure safety and ethical use of stem cells in neurological disorders.
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Affiliation(s)
- M Gourie Devi
- Department of Neurology, Institute of Human Behavior and Allied Sciences, New Delhi, India
| | - Alka Sharma
- Department of Biotechnology, Government of India, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Neeraj Jain
- National Brain Research Institute, Gurgaon, Haryana, India
| | - Kusum Verma
- Department of Pathology, Sir Ganga Ram Hospital, New Delhi, India
| | - M Vasantha Padma
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Pramod Pal
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - H S Chabbra
- Indian Spinal Injuries Center, New Delhi, India
| | - Satish Khadilkar
- Department of Neurology, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Sudesh Prabhakar
- Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Gagandeep Singh
- Department of Neurology, Dayanand Medical College, Ludhiana, Punjab, India
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Lindvall O. Treatment of Parkinson's disease using cell transplantation. Philos Trans R Soc Lond B Biol Sci 2016; 370:20140370. [PMID: 26416681 DOI: 10.1098/rstb.2014.0370] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long-lasting improvement. However, owing to poor tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies.
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Affiliation(s)
- Olle Lindvall
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, University Hospital, 221 84 Lund, Sweden
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40
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Abstract
In Parkinson's disease (PD), the main pathology underlying the motor symptoms is a loss of nigrostriatal dopaminergic neurons. Clinical trials of intrastriatal transplantation of human foetal mesencephalic tissue have shown that the grafted dopaminergic neurons re-innervate the striatum, restore striatal dopamine release and, in some cases, induce major, long-lasting improvement of motor function. However, nonmotor symptoms originating from degeneration outside the striatum or in nondopaminergic systems are not alleviated by intrastriatal implantation of dopaminergic neurons. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation in patients with PD. Recent studies demonstrate that standardized preparations of dopaminergic neurons of the correct substantia nigra phenotype can be generated from human embryonic stem cells in large numbers, and they will soon be available for patient application. In addition, dopaminergic neurons derived from human induced pluripotent stem cells are being considered for clinical translation. Important challenges include the demonstration of potency (growth capacity and functional efficacy) and safety of the generated dopaminergic neurons in preclinical animal models. The dopaminergic neurons should subsequently be tested, using optimal patient selection and cell preparation and transplantation procedures, in controlled clinical studies.
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Affiliation(s)
- O Lindvall
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, University Hospital, Lund, Sweden
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Foetal Cell Transplantation for Parkinson's Disease: Focus on Graft-Induced Dyskinesia. PARKINSONS DISEASE 2015; 2015:563820. [PMID: 26881178 PMCID: PMC4736211 DOI: 10.1155/2015/563820] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 12/02/2015] [Accepted: 12/16/2015] [Indexed: 02/05/2023]
Abstract
Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson's disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID.
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Chen Z. Cell Therapy for Parkinson's Disease: New Hope from Reprogramming Technologies. Aging Dis 2015; 6:499-503. [PMID: 26618051 DOI: 10.14336/ad.2014.1201] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 12/01/2014] [Indexed: 12/16/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with the major pathology being the progressive loss of dopaminergic (DA) midbrain neurons in the substantia nigra. As early as in the 1980s, open-label clinical trials employing fetal ventral mesencephalon (fVM) tissues have demonstrated significant efficacy for PD treatment, which led to two NIH-sponsored double-blind placebo-controlled clinical trials. However, both trials showed only mild outcome. Retrospective analysis revealed several possible reasons that include patient selection, heterogeneity of grafts, immune recognition of grafts, lack of standardization of transplantation procedure and uneven distribution of grafts. Recent years have seen advances in reprogramming technologies which may provide solutions to the problems associated with fVM tissues. Induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) hold promise for generating clinical grade DA neural cells that are safe, homogeneous, scalable and standardizable. These new technologies may bring back clinical trials using cell therapy for PD treatment in the future.
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Affiliation(s)
- Zhiguo Chen
- 1 Cell Therapy Center, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China ; 2 Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China ; 3 Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
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Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat Rev Neurol 2015; 11:492-503. [PMID: 26240036 DOI: 10.1038/nrneurol.2015.123] [Citation(s) in RCA: 218] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.
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Affiliation(s)
- Roger A Barker
- John van Geest Centre for Brain Repair &Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK
| | - Janelle Drouin-Ouellet
- Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11, S-221 84 Lund, Sweden
| | - Malin Parmar
- Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11, S-221 84 Lund, Sweden
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Borlongan CV, Jolkkonen J, Detante O. The future of stem cell therapy for stroke rehabilitation. FUTURE NEUROLOGY 2015; 10:313-319. [PMID: 26997918 DOI: 10.2217/fnl.15.27] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Cesar V Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612 USA
| | - Jukka Jolkkonen
- University of Eastern Finland, Institute of Clinical Medicine - Neurology, Yliopistonranta 1 C, 70210 Kuopio, Finland
| | - Olivier Detante
- University Hospital of Grenoble, Stroke Unit, Department of Neurology, CS 10217, 38043 Grenoble, France; Inserm, U 836, BP 170, 38042 Grenoble, France; University Grenoble Alpes, Grenoble Institute of Neurosciences, BP 170, 38042 Grenoble, France
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Aron Badin R, Vadori M, Cozzi E, Hantraye P. Translational research for Parkinson׳s disease: The value of pre-clinical primate models. Eur J Pharmacol 2015; 759:118-26. [DOI: 10.1016/j.ejphar.2015.03.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/10/2015] [Accepted: 03/12/2015] [Indexed: 12/15/2022]
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Abstract
Stem cell-based therapies hold considerable promise for many currently devastating neurological disorders. Substantial progress has been made in the derivation of disease-relevant human donor cell populations. Behavioral data in relevant animal models of disease have demonstrated therapeutic efficacy for several cell-based approaches. Consequently, cGMP grade cell products are currently being developed for first in human clinical trials in select disorders. Despite the therapeutic promise, the presumed mechanism of action of donor cell populations often remains insufficiently validated. It depends greatly on the properties of the transplanted cell type and the underlying host pathology. Several new technologies have become available to probe mechanisms of action in real time and to manipulate in vivo cell function and integration to enhance therapeutic efficacy. Results from such studies generate crucial insight into the nature of brain repair that can be achieved today and push the boundaries of what may be possible in the future.
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47
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Barker RA. What have open label studies of cell based therapies for Parkinson's disease told us, if anything? ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.baga.2014.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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48
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Remy P. Biotherapies for Parkinson disease. Rev Neurol (Paris) 2014; 170:763-9. [DOI: 10.1016/j.neurol.2014.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 10/08/2014] [Indexed: 11/17/2022]
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Cell based therapies in Parkinson's Disease. Ann Neurosci 2014; 18:76-83. [PMID: 25205926 PMCID: PMC4117039 DOI: 10.5214/ans.0972.7531.1118209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2011] [Revised: 04/09/2011] [Accepted: 04/30/2011] [Indexed: 12/27/2022] Open
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is characterized by bradykinesia, hypokinesia/ akinesia, rigidity, tremor, and postural instability, caused by dopaminergic (DA) striatal denervation. The prevalence of PD increases from 50 years of age with steep rise after age 60 years. Current treatment of PD relies heavily on replacing lost dopamine either with its precursor L-dopa or dopamine agonists (ropinirole, pramipexole, bromocriptine, lisuride etc). Other pharmacological measures like catechol-O-methyltrasferase (COMT) inhibitors like entacopone, telcapone and monoamine oxidase B (MAO-B) inhibitors like selegiline and rasagiline are also useful, while L-dopa remains the gold standard in the treatment of PD. Emerging therapies are focusing on cell based therapeutics derived from various sources.
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Canet-Aviles R, Lomax GP, Feigal EG, Priest C. Proceedings: cell therapies for Parkinson's disease from discovery to clinic. Stem Cells Transl Med 2014; 3:979-91. [PMID: 25150264 DOI: 10.5966/sctm.2014-0146] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In March 2013, the California Institute for Regenerative Medicine, in collaboration with the NIH Center for Regenerative Medicine, held a 2-day workshop on cell therapies for Parkinson's disease (PD), with the goals of reviewing the state of stem cell research for the treatment of PD and discussing and refining the approach and the appropriate patient populations in which to plan and conduct new clinical trials using stem cell-based therapies for PD. Workshop participants identified priorities for research, development, and funding; discussed existing resources and initiatives; and outlined a path to the clinic for a stem cell-based therapy for PD. A consensus emerged among participants that the development of cell replacement therapies for PD using stem cell-derived products could potentially offer substantial benefits to patients. As with all stem cell-based therapeutic approaches, however, there are many issues yet to be resolved regarding the safety, efficacy, and methodology of transplanting cell therapies into patients. Workshop participants agreed that designing an effective stem cell-based therapy for PD will require further research and development in several key areas. This paper summarizes the meeting.
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Affiliation(s)
- Rosa Canet-Aviles
- California Institute for Regenerative Medicine, San Francisco, California, USA
| | - Geoffrey P Lomax
- California Institute for Regenerative Medicine, San Francisco, California, USA
| | - Ellen G Feigal
- California Institute for Regenerative Medicine, San Francisco, California, USA
| | - Catherine Priest
- California Institute for Regenerative Medicine, San Francisco, California, USA
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