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Progress and prospects: stem cells and neurological diseases
Gene Ther. 2011 Jan;18(1):1-6.
Source
Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, UK.
stefanie.gogel@kcl.ac.uk
Abstract
The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.
Stem cells as therapeutics for neurodegenerative disorders
Expert Rev Neurother. 2001 Nov;1(2):267-73.
Source
Laboratory of Neurosciences, National Institute on Aging GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
mattsonm@grc.nia.nih.gov
Abstract
Aging is associated with a progressive increase in the risk of several prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke and amyotrophic lateral sclerosis. In each of these disorders specific populations of neurons become dysfunctional, then die and are not replaced. The adult brain and spinal cord contain populations of so-called neural stem cells (self-renewing and multipotent) and neural precursor cells (specified to a certain fate, but still mitotic) that may provide a continuing source of new neurons and glial cells during successful aging and after injury to the nervous system. Recent studies have shown that stem cells from embryos and adults can be transplanted into the nervous system, differentiate into neurons and glia and restore lost function in experimental models of neurodegenerative diseases. Embryonic stem cells may be a particularly effective donor cell type for transplantation-based therapies. Efficacy of stem cell therapies remains to be established in clinical trials in humans. Another approach is to mobilize endogenous neural stem cells. Animals studies have shown that dietary and behavioral modifications can indeed stimulate neurogenesis. Molecular and cellular mechanisms that regulate the proliferation, differentiation and survival of neural stem cells and neural precursor cells are being elucidated and are revealing novel targets for the development of pharmaceuticals that promote neurogenesis.
Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery
Curr Med Chem. 2010;17(8):759-66.
Source
Center of Physiology and Pathophysiology, Institute of Neurophysiology, and Center of Molecular Medicine, University of Cologne (CMMC), Robert-Koch Str. 39, Cologne, Germany.
Abstract
Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson's disease, Alzheimer's disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient's blood cells or cells from biopsies, obviating the need for cellular delivery of reprogramming exogenous transgenes, thereby converting hope into reality for patients suffering from degenerative diseases. Patients worldwide stand to benefit from the clinical applicability of iPS cell-based cell replacement therapy for a number of degenerative diseases. The second is the potential for discovering novel drugs in a high throughput manner using patient-specific iPS cell-derived somatic cells possessing the etiology of the specific disease. The third is their suitability for toxicological testing of drugs and environmental factors. This review focuses on these potential applications of iPS cells with special emphasis on recent updates of iPS cell research contributing to the accelerated drug discovery.
Gene- and cell-based approaches for neurodegenerative disease
Adv Exp Med Biol. 2010;671:117-30.
Source
Department of Radiation Oncology, Univesity of Michigan, Ann Arbor, Michigan, USA.
kurbania@med.umich.edu
Abstract
Neurodegenerative diseases comprise an important group ofchronic diseases that increase in incidence with rising age. In particular, the two most common neurodegenerative diseases are Alzheimer's disease and Parkinson's disease, both of which will be discussed below. A third, Huntington's disease, occurs infrequently, but has been studied intensely. Each of these diseases shares characteristics which are also generalizeable to other neurodegenerative diseases: accumulation ofproteinaceous substances that leads inexorably to selective neuronal death and decline in neural function. Treatments for these diseases have historically focused on symptomatic relief, but recent advances in molecular research have identified more specific targets. Additionally, stem cell therapy, immunotherapy and trophic-factor delivery provide avenues for neuronal protection that may alter the natural progression of these devastating illnesses. Upcoming clinical trials will evaluate treatment strategies and provide hope that translational research will decrease the onset of debilitating disability associated with neurodegenerative disease.
Human tooth germ stem cells preserve neuro-protective effects after long-term cryo-preservation
Curr Neurovasc Res. 2010 Feb;7(1):49-58.
Mehmet E Yalvaç, Mustafa Ramazanoglu, Murat Tekguc, Omer F Bayrak, Aygul K Shafigullina, Ilnur I Salafutdinov, Natalia L Blatt, Andrey P Kiyasov, Fikrettin Sahin, András Palotás, Albert A Rizvanov
Source
Department of Genetics and BioEngineering, College of Engineering and Architecture, Yeditepe University, Campus, Kayisdagi cad., Kayisdagi, TR-34755 Istanbul, Turkey.
Abstract
The use of mesenchymal stem cells (MSCs) has been shown to be promising in chronic disorders such as diabetes, Alzheimer's dementia, Parkinson's disease, spinal cord injury and brain ischemia. Recent studies revealed that human tooth germs (hTG) contain MSCs which can be easily isolated, expanded and cryo-preserved. In this report, we isolated human tooth germ stem cells (hTGSCs) with MSC characteristics from third molar tooth germs, cryo-preserved them at -80( degrees )C for 6 months, and evaluated for their surface antigens, expression of pluri-potency associated genes, differentiation capacity, karyotype, and proliferation rate. These characteristics were compared to their non-frozen counterparts. In addition, neuro-protective effects of cryo-preserved cells on neuro-blastoma SH-SY5Y cells were also assessed after exposure to stress conditions induced by hydrogen-peroxide (oxidative stress) and paclitaxel (microtubule stabilizing mitotic inhibitor). After long term cryo-preservation hTGSCs expressed surface antigens CD29, CD73, CD90, CD105, and CD166, but not CD34, CD45 or CD133, which was typical for non-frozen hTGSCs. Cryo-preserved hTGSCs were able to differentiate into osteo-, adipo- and neuro-genic cells. They also showed normal karyotype after high number of population doublings and unchanged proliferation rate. On the other hand, cryo-preserved cells demonstrated a tendency for lower level of pluri-potency associated gene expression (nanog, oct4, sox2, klf4, c-myc) than non-frozen hTGSCs. hTGSCs conditioned media increased survival of SH-SY5Y cells exposed to oxidative stress or paclitaxel. These findings confirm that hTGSCs preserve their major characteristics and exert neuro-protection after long-term cryo-preservation, suggesting that hTGSCs, harvested from young individuals and stored for possible use later as they grow old, might be employed in cellular therapy of age-related degenerative disorders.
Translation of stem cell therapy for neurological diseases
Transl Res. 2010 Sep;156(3):155-60.
Source
Department of Neurology, University of Leipzig, Leipzig, Germany.
Abstract
"Regenerative medicine" hopefully will provide novel therapies for diseases that remain without effective therapy. This development is also true for most neurodegenerative disorders including Alzheimer's disease, Huntington's disease, or Parkinson's disease. Transplantation of new neurons to the brain has been performed in Parkinson's disease and in Huntington's disease. The restoration of dopaminergic neurons in patients with Parkinson's disease via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications, showing a limited efficacy. Clinical trials in patients with Huntington's disease using fetal striatal tissue currently are underway. Today, it seems possible to generate functional dopaminergic or striatal neurons form a variety of stem cells including embryonic or neural stem cells as well as induced pluripotent stem cells. First clinical trials using neural stem cell or embryonic-stem-cell-derived tissue are approved or already underway. Such cells allow for extensive in vitro and in vivo testing as well as "good manufacturing production," reducing the risks in clinical application.
Ageing and neurodegenerative diseases
Ageing Res Rev. 2010 Nov;9 Suppl 1:S36-46.
Source
Department of Neurology, Zhongxiao Branch, Taipei City Hospital/No 87, Tongde Rd, Nangang Dist, Taipei City 115, Taiwan.
Abstract
Ageing, which all creatures must encounter, is a challenge to every living organism. In the human body, it is estimated that cell division and metabolism occurs exuberantly until about 25 years of age. Beyond this age, subsidiary products of metabolism and cell damage accumulate, and the phenotypes of ageing appear, causing disease formation. Among these age-related diseases, neurodegenerative diseases have drawn a lot of attention due to their irreversibility, lack of effective treatment, and accompanied social and economical burdens. In seeking to ameliorate ageing and age-related diseases, the search for anti-ageing drugs has been of much interest. Numerous studies have shown that the plant polyphenol, resveratrol (3,5,4'-trihydroxystilbene), extends the lifespan of several species, prevents age-related diseases, and possesses anti-inflammatory, and anti-cancer properties. The beneficial effects of resveratrol are believed to be associated with the activation of a longevity gene, SirT1. In this review, we discuss the pathogenesis of age-related neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and cerebrovascular disease. The therapeutic potential of resveratrol, diet and the roles of stem cell therapy are discussed to provide a better understanding of the ageing mystery.
Progress and prospects: stem cells and neurological diseases
Gene Ther. 2011 Jan;18(1):1-6.
Source
Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, UK.
stefanie.gogel@kcl.ac.uk
Abstract
The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.
Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients
Mol Biol Rep. 2019 Oct;46(5):5257-5272.
Christopher Duma, Oleg Kopyov, Alex Kopyov, Mark Berman, Elliot Lander, Michael Elam, Michael Arata, David Weiland, Ruslana Cannell, Chad Caraway, Sean Berman, Kristin Scord, Lian Stemler, Karlyssa Chung, Samuel Khoudari, Rory McRory, Chace Duma, Sawyer Farmer, Anthony Bravo, Christian Yassa, Ami Sanathara, Elisa Singh, Benjamin Rapaport
Source
Neurosurgery, Brain and Spine Surgeons of Orange County, Newport Beach, CA, USA.
cduma@brainandspineoc.com.
Abstract
We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.
Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in refractory Takayasu arteritis: a retrospective multicenter case-series from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Bone Marrow Transplant. 2020 Nov;55(11):2109-2113.
Charlotte Laurent, Zora Marjanovic, Laure Ricard, Joerg Henes, Remy Dulery, Manuela Badoglio, Dominique Farge, John A Snowden, Daniela Moraes, Juliana Dias, Mohamad Mohty, Michael Soussan, Olivier Fain, Renate Arnold, Tobias Alexander, Maria-Carolina Oliveira, Arsène Mekinian
Source
Sorbonne Université, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU i3), Hôpital Saint-Antoine, APHP, F-75012, Paris, France.
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment option in severely affected and refractory patients with autoimmune diseases. This is a retrospective survey of patients reported to the EBMT registry between 1998 and 2019, who received AHSCT for TAK. Data from six patients treated with AHSCT for refractory TAK have been identified, five were female (83%), median age 25 (9-39) years. All patients were pretreated with a median of 6 (4-8) lines of therapy, including steroids (six patients), methotrexate (five patients), cyclophosphamide, mycophenolate mofetil or infliximab (four patients), tocilizumab or etanercept (two patients). Conditioning included cyclophosphamide and rabbit anti-thymocyte globulin in all patients. At 6 months post transplantation, remission was obtained in all cases, which persisted at 12 months in five cases. Four patients reactivated TAK at a median time of 27 (7-52) months after AHSCT, and three resumed disease-modifying therapy. At last follow-up, all patients were alive, two patients were in remission (off-therapy), two patients improved compared with baseline, and two patients were in complete and partial remission, respectively, under immunosuppressive treatment. This retrospective case-series demonstrates that AHSCT has the potential to provide significant clinical responses in TAK patients, but large prospective trials are necessary to confirm these preliminary data.
Mesenchymal stem cell transplantation: a potential therapy for oral lichen planus
Med Hypotheses. 2011 Mar;76(3):322-4.
Source
Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing 100050, China.
Abstract
Oral lichen planus is a type of T cell-mediated autoimmune disease. Satisfactory therapy results are not usually achieved with conventional treatment; however, a new therapy employing T cell immune modulation may treat this disease. Mesenchymal stem cells are multipotent nonhematopoietic progenitor cells that are capable of self-renewal and differentiation into various cell types, including osteocytes and adipocytes. Thus, mesenchymal stem cells are regarded as a promising cell population for tissue regeneration in the clinic. In the past several years, there has been a dramatic improvement in the understanding of immunosuppressive properties of mesenchymal stem cells on various immune cell types. We propose that mesenchymal stem cells can be utilized to treat oral lichen planus patients via systemic infusion or local application.
Research advances in amyotrophic lateral sclerosis
Curr Neurol Neurosci Rep. 2011 Feb;11(1):67-77.
Source
Eleanor and Lou Gehrig MDA/ALS Research Center, Neurological Institute, Columbia University Medical Center, 710 West 168th Street, New York, NY 10032, USA.
rt2238@columbia.edu
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons that causes progressive weakness and death. The breadth of research in ALS continues to grow with exciting new discoveries in disease pathogenesis and potential future therapeutics. There is a growing list of identified mutations in familial ALS, including those in genes encoding TDP-43 and FUS/TLS, which are expanding our understanding of the role of RNA modulation in ALS pathogenesis. There is a greater appreciation for the role of glial cells in motor neuron disease. Mitochondrial dysfunction is also being shown to be critical for motor neuron degeneration. In addition to pharmacotherapy, there are promising early developments with therapeutic implications in the areas of RNA interference, stem cell therapies, viral vector-mediated gene therapy, and immunotherapy. With greater understanding of ALS pathogenesis and exciting new therapeutic technologies, there is hope for future progress in treating this disease.
Multiple sclerosis - established and novel therapeutic approaches
Cent Nerv Syst Agents Med Chem. 2010 Mar;10(1):3-15.
Source
Clinical Department of Neurology, Innsbruck Medical University, Austria.
Abstract
Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.
Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients
Mol Biol Rep. 2019 Oct;46(5):5257-5272.
Christopher Duma, Oleg Kopyov, Alex Kopyov, Mark Berman, Elliot Lander, Michael Elam, Michael Arata, David Weiland, Ruslana Cannell, Chad Caraway, Sean Berman, Kristin Scord, Lian Stemler, Karlyssa Chung, Samuel Khoudari, Rory McRory, Chace Duma, Sawyer Farmer, Anthony Bravo, Christian Yassa, Ami Sanathara, Elisa Singh, Benjamin Rapaport
Source
Neurosurgery, Brain and Spine Surgeons of Orange County, Newport Beach, CA, USA.
cduma@brainandspineoc.com.
Abstract
We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.
Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy
Neuropharmacology. 2010 May;58(6):855-64.
Source
Department of Biology and Program in Neuroscience and Behavior, Hall Atwater Laboratory, 52 Lawn Avenue, Wesleyan University, Middletown, CT 06459, USA.
jnaegele@wesleyan.edu
Abstract
The potential applications of stem cell therapies for treating neurological disorders are enormous. Many laboratories are focusing on stem cell treatments for CNS diseases, including spinal cord injury, Amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, traumatic brain injury, and epilepsy. Among the many stem cell types under testing for neurological treatments, the most common are fetal and adult brain stem cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. An expanding toolbox of molecular probes is now available to allow analyses of neural stem cell fates prior to and after transplantation. Concomitantly, protocols are being developed to direct the fates of stem cell-derived neural progenitors, and also to screen stem cells for tumorigenicity and aneuploidy. The rapid progress in the field suggests that novel stem cell and gene therapies for neurological disorders are in the pipeline.
The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells
Cell Transplant. 2011;20(1):85-94.
Paul R Sanberg, David J Eve, Alison E Willing, Svitlana Garbuzova-Davis, Jun Tan, Cyndy D Sanberg, Julie G Allickson, L Eduardo Cruz, Cesar V Borlongan
Source
Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA.
psanberg@health.usf.edu
Abstract
Stem cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent, and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement, have been detected in both transplanted cells.
Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases
Expert Opin Biol Ther. 2009 Dec;9(12):1487-97.
Source
Neurosciences Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.
Abstract
Background: Stem-cell-based therapy is a promising new approach to handling neurodegenerative diseases. One of the most promising cellular sources is bone-marrow-derived mesenchymal stem cells (MSCs) also termed multipotent stromal cells. MSCs represent an autologous source and are abundant and non-tumorigenic. Additionally, MSCs possess the useful characteristics of homing and chemokine secretion.
Objective/methods: Since neurodegenerative diseases have many pathological processes in common, a specific therapeutic agent could potentially ameliorate the symptoms of several distinct neurodegenerative diseases. In this review we demonstrate the wide variety of mechanisms by which MSCs can influence neurodegenerative processes.
Results/conclusions: The mechanisms by which transplanted MSCs influence neurodegenerative diseases can be broadly classified as cellular replacement or paracrine secretion, with the latter subdivided into trophic factor secretion or immunomodulation by cytokines. Emerging research suggests that genetic manipulations before transplantation could enhance the therapeutic potential of MSCs. Such manipulation could turn the cells into a 'Trojan horse', to deliver specific proteins, or promote reprogramming of the MSCs into the neural lineage. Clinical trials testing MSC-based therapies for familial amyotrophic lateral sclerosis and multiple sclerosis are in progress.
Stem cell-based cell therapy in neurological diseases: a review
J Neurosci Res. 2009 Aug 1;87(10):2183-200.
Source
Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
sukim@interchange.ubc.ca
Abstract
Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.
Cerebral palsy-brain repair with stem cells
J Perinat Med. 2022 Dec 12.
Source
Campus Clinic Gynecology, Ruhr-University Bochum, Bochum, Germany.
Abstract
Cerebral palsy, the most common disability in childhood, is a devastating non-progressive ailment of the infants' brain with lifelong sequelae, e.g., spastic paresis, chronic pain, inability to walk, intellectual disability, behavioral disorders, for which there is no cure at present. CP may develop after pediatric brain damage caused, e.g., by hypoxic-ischemia, periventricular leukomalacia, intracranial hemorrhage, hypoxic-ischemic encephalopathy, trauma, stroke, and infection. About 17 million people worldwide live with cerebral palsy as a result of pediatric brain damage. This reflects both the magnitude of the personal, medical, and socioeconomic global burden of this brain disorder and the overt unmet therapeutic needs of the pediatric population. This review will focus on recent preclinical, clinical, and regulatory developments in cell therapy for infantile cerebral palsy by transplantation of cord blood derived mononuclear cells from bench to bedside. The body of evidence suggests that cord blood cell therapy of cerebral palsy in the autologous setting is feasible, effective, and safe, however, adequately powered phase 3 trials are overdue.
Stem cells therapy in cerebral palsy: A systematic review
Brain Dev. 2016 Sep;38(8):699-705.
Source
Department of Pediatric Rehabilitation, Medical University of Bialystok, Białystok, Poland.
Abstract
The aim of this study was to systematically present the best available stem cell therapies for children with cerebral palsy (CP). The databases Medline, PubMed, EMBASE, and the Cochrane Controlled Trials Register for RCTs were searched for studies published from 1967 to August 2015. Systematic reviews, randomised controlled trials (RCTs), controlled trials, uncontrolled trials, cohort studies, open-label studies, and a meta-analysis were analysed. Of 360 articles, seven fulfilled the inclusion criteria: one RCT and six were open-label trials. In these studies, one application of stem cells for children with CP was typical, and the total number of cells administered to patients ranged from 10(6) to 10(8)/kg. Different routes of cell delivery were used, though in most studies motor development was applied as an indicator of primary outcomes. In three articles, neuroimaging studies were also implemented to confirm the efficacy of the therapies. Observation periods varied from 3months to 5years, and patients' tolerance of the therapy was generally good. Stem cell therapy may improve some symptoms in patients with CP, though larger studies are needed to examine the impact of stem cell therapy upon CP.
Progress in clinical trials of stem cell therapy for cerebral palsy
Neural Regen Res. 2021 Jul;16(7):1377-1382.
Source
Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China.
Abstract
Cerebral palsy is the most common disease in children associated with lifelong disability in many countries. Clinical research has demonstrated that traditional physiotherapy and rehabilitation therapies cannot alone cure cerebral palsy. Stem cell transplantation is an emerging therapy that has been applied in clinical trials for a variety of neurological diseases because of the regenerative and unlimited proliferative capacity of stem cells. In this review, we summarize the design schemes and results of these clinical trials. Our findings reveal great differences in population characteristics, stem cell types and doses, administration methods, and evaluation methods among the included clinical trials. Furthermore, we also assess the safety and efficacy of these clinical trials. We anticipate that our findings will advance the rational development of clinical trials of stem cell therapy for cerebral palsy and contribute to the clinical application of stem cells.
The potential for stem cells in cerebral palsy--piecing together the puzzle
Semin Pediatr Neurol. 2013 Jun;20(2):146-53.
Source
Center of Physiology and Pathophysiology, Institute of Neurophysiology, and Center of Molecular Medicine, University of Cologne (CMMC), Robert-Koch Str. 39, Cologne, Germany.
Abstract
The substantial socioeconomic burden of a diagnosis of cerebral palsy, coupled with a positive anecdotal and media spin on stem cell treatments, drives many affected families to seek information and treatment outside of the current clinical and scientific realm. Preclinical studies using several types of stem and adult cells--including mesenchymal stem cells, neural precursor cells, olfactory ensheathing glia and Schwann cells--have demonstrated some regenerative and functional efficacy in neurologic paradigms. This paper describes the most common cell types investigated for transplant in vivo and summarizes the current state of early-phase clinical trials. It investigates the most relevant and promising coadministered therapies, including rehabilitation, drug targeting, magnetic stimulation, and bioengineering approaches. We highlight the need for adjunctive combinatorial strategies to successfully transfer stem cell treatments from bench to bedside.
Stem cell therapies in cerebral palsy and autism spectrum disorder
Dev Med Child Neurol. 2021 May;63(5):503-510.
Source
The Marcus Center for Cellular Cures, Duke University, Durham, NC, USA.
Abstract
Across disciplines, there is great anticipation that evolving cell therapies may finally provide a therapeutic option for conditions in dire need. These conditions are typically complex and their pathophysiology incompletely understood, hindering the development of robust preclinical models and the precise assessment of therapeutic effects in human studies. This article provides an overview of the status of cell therapy investigations in two common neurodevelopmental disorders, cerebral palsy and autism spectrum disorder. Challenges facing this line of study, including inherent heterogeneity, knowledge gaps, and unrealistic expectations, are discussed. Much progress has been made in the past decade, but to definitively determine if cell therapies have a role in the treatment of neurodevelopmental disorders, both fields will need to evolve together. WHAT THIS PAPER ADDS: The safety profile of reported cell therapies in children with neurodevelopmental disorders is encouraging. Efficacy trials in cerebral palsy and autism spectrum disorder are ongoing in the United States and Asia. Unresolved issues pertain to the properties of the cells being studied and the characteristics of the neurodevelopmental conditions themselves.
The Role of Stem Cells in the Treatment of Cerebral Palsy: a Review
Mol Neurobiol. 2017 Sep;54(7):4963-4972.
Anahita Kiasatdolatabadi, Nasrin Lotfibakhshaiesh, Meysam Yazdankhah, Somayeh Ebrahimi-Barough, Mina Jafarabadi, Arman Ai, Esmaeil Sadroddiny, Jafar Ai
Source
Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of medical sciences, 88, 10th floor, Italia Str., Keshavarz Blv, Tehran, Iran.
Abstract
Cerebral palsy (CP) is a neuromuscular disease due to injury in the infant's brain. The CP disorder causes many neurologic dysfunctions in the patient. Various treatment methods have been used for the management of CP disorder. However, there has been no absolute cure for this condition. Furthermore, some of the procedures which are currently used for relief of symptoms in CP cause discomfort or side effects in the patient. Recently, stem cell therapy has attracted a huge interest as a new therapeutic method for treatment of CP. Several investigations in animal and human with CP have demonstrated positive potential of stem cell transplantation for the treatment of CP disorder. The ultimate goal of this therapeutic method is to harness the regenerative capacity of the stem cells causing a formation of new tissues to replace the damaged tissue. During the recent years, there have been many investigations on stem cell therapy. However, there are still many unclear issues regarding this method and high effort is needed to create a technology as a perfect treatment. This review will discuss the scientific background of stem cell therapy for cerebral palsy including evidences from current clinical trials.
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