ALS Amyotrophic Lateral Sclerosis
 
     ALS also known as Lou Gehrig’s disease is a debilitating neurologic disease that results from the destruction of upper and lower motor neurons in the brain and spinal cord. ALS is associated with rapidly progressive weakness, muscle wasting, spasticity, and difficulty breathing, swallowing and speaking. There is no known cause for ALS and genetics are implicated in only 5% of cases. There is no known cure for the physical defects associated with ALS. Many investigators are looking at using the regenerative properties of cell therapy to mitigate the impact of ALS on the nervous system.
 

     We use a specific SVF deployment protocol that attempts to utilize the immuno-regulatory, regenerative, and anti-inflammatory properties of SVF (rich in mesenchymal stem cells and growth factors). Special measures are taken to optimize transport of the SVF across the blood-brain barrier to improve central nervous system uptake. This is all done as an outpatient at the time of SVF harvesting and procurement. The entire cellular surgical procedure takes approximately three hours.

     We care about our ALS patients and take pride in the time we provide to our patients to deploy the best protocols to help our patients achieve their goals. By filling out a Confidential Candidate Application, we will answer the questions and concerns you may have about our Stem Cell Treatment Centers and Cell Surgical Network protocols for ALS.
 
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Cell-replacement therapy with stem cells in neurodegenerative diseases.

Curr Neurovasc Res. 2004 Jul;1(3):283-9.

Cell-replacement therapy with stem cells in neurodegenerative diseases.

Silani V, Corbo M.

Department of Neurology and Laboratory of Neuroscience – Dino Ferrari Center, University of Milan Medical School – IRCCS Istituto Auxologico Italiano. vincenzo@silani.com

Abstract
In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.
PMID: 16181078 [PubMed – indexed for MEDLINE]

 
Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.

Arch Neurol. 2010 Oct;67(10):1187-94.
Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JW, Petrou P, Ben-Hur T, Abramsky O, Slavin S.
Department of Neurology, Hadassah-Hebrew University Hospital, Ein Karem, Jerusalem IL-91120, Israel. karus@cc.huji.ac.il
Abstract
OBJECTIVE: To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).
DESIGN: A phase 1/2 open-safety clinical trial. Patients Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex).
MAIN OUTCOME MEASURES: The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation.
RESULTS: Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation.
CONCLUSION: Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration clinicaltrials.gov Identifier: NCT00781872.
PMID: 20937945 [PubMed – indexed for MEDLINE]

 
Stem cells in amyotrophic lateral sclerosis: state of the art.

Expert Opin Biol Ther. 2009 Oct;9(10):1245-58.
Stem cells in amyotrophic lateral sclerosis: state of the art.
Mazzini L, Vercelli A, Ferrero I, Mareschi K, Boido M, Servo S, Oggioni GD, Testa L, Monaco F, Fagioli F.
Eastern Piedmont University, Maggiore della Carità Hospital, ALS Centre, Department of Neurology, Corso Mazzini 18, Novara 28100, Italy. mazzini.l@libero.it
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurodegenerative disease that targets motor neurons, manifesting as a linear decline in muscular function and leading to death within 2 – 5 years of diagnosis. The vast majority of ALS cases are sporadic, the aetiopathology of which is incompletely understood. Recent data have implicated the microenvironment of the motor neuron as a primary target of the pathophysiology. Any experimental therapeutic approach to ALS is very difficult because of some peculiarities of the disease, such as the unknown origin, the spatial diffusion of motor neuron loss and the paucity of animal models. Despite such daunting challenges, in experimental models a number of potential benefits of stem cells in ALS therapy have been demonstrated: by providing non-compromised supporting cells such as astrocytes, microglia or growth factor-excreting cells, onset can be delayed and survival increased. Moreover, in animal models of acute or chronic motor neuron injury, neural stem cells implanted into the spinal cord have been shown to differentiate into motor neurons, with some evidence of axonal sprouting and formation of nerumuscular junctions with host muscle. Here we summarise and discuss current preclinical and clinical evidence regarding stem cells application in ALS, particularly focusing on methodological issues.
PMID: 19663719 [PubMed – indexed for MEDLINE]

 
Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients.

Cytotherapy. 2009;11(1):26-34.

Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients.

Martinez HR, Gonzalez-Garza MT, Moreno-Cuevas JE, Caro E, Gutierrez-Jimenez E, Segura JJ.

Servicio de Neurologia, Hospital Universitario UANL, Monterrey, Mexico. drhectormtz@yahoo.com

Abstract
BACKGROUND AIMS: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons. CD133(+) stem cells are known to have the capacity to differentiate into neural lineages. Stem cells may provide an alternative treatment for ALS and other neurodegenerative diseases.
METHODS: Five men and five women (aged 38-62 years) with confirmed ALS were included in this study. Our institutional ethics and research committees approved the protocol. After informed consent was obtained, patients underwent Hidrogen-Magnetic Resonance Imaging (H-MRI) spectroscopy and were given scores according to an ALS functional rating scale, Medical Research Council power muscle scale and daily living activities. Bone marrow was stimulated with 300 microg filgrastim subcutaneously daily for 3 days. Peripheral blood mononuclear cells were obtained after admission by leukapheresis. The cell suspension was conjugated with anti-human CD133 superparamagnetic microbeads, and linked cells were isolated in a magnetic field. The isolated cells (2.5-7.5×10(5)) were resuspended in 300 microL of the patient’s cerebrospinal fluid, and implanted in motor cortexes using a Hamilton syringe. Ten patients with confirmed ALS without transplantation were used as a control group. Patients were followed up for a period of 1 year.
RESULTS: The autologous transplantation of CD133(+) stem cells into the frontal motor cortex is a safe and well-tolerated procedure in ALS patients. The survival of treated patients was statistically higher (P=0.01) than untreated control patients.
CONCLUSIONS: Stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life.
PMID: 19191058 [PubMed – indexed for MEDLINE]

 


Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS.
 
 Neurology. 2016 Nov 22;87(21):2230-2234. Epub 2016 Oct 26. Authors: Staff NP, Madigan NN, Morris J, Jentoft M, Sorenson EJ, Butler G, Gastineau D, Dietz A, Windebank AJ.

Abstract
 
OBJECTIVE: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS).

 

METHODS: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 107 (single dose) to 1 × 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis.

 

RESULTS: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients.

 

CONCLUSIONS: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials.This  study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe.

 

 
Advances in stem cell research for Amyotrophic Lateral Sclerosis.

Curr Opin Biotechnol. 2009 Oct;20(5):545-51. Epub 2009 Oct 12.
Advances in stem cell research for Amyotrophic Lateral Sclerosis.
Papadeas ST, Maragakis NJ.
Johns Hopkins University, 600 N. Wolfe St., Meyer 6-119, Baltimore, MD 21287, USA.
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized primarily by motor neuron loss in the motor cortex and spinal cord leading to progressive disability and death. Despite the relative selectivity of motor neuron loss, recent studies have implicated other cell types including astrocytes and microglia as contributors to this cell death. This understanding has resulted in stem-cell-replacement strategies of these cell types, which may result in neuroprotection. In addition to cell-replacement strategies, the development of induced pluripotent stem cell (iPSC) technologies has resulted in the establishment of motor neuron cell lines from patients with ALS. The use of iPSCs from ALS patients will allow for potential autologous cell transplantation, drug discovery, and an increased understanding of ALS pathobiology.
PMID: 19819686 [PubMed – indexed for MEDLINE]

 
Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial.

Exp Neurol. 2010 May;223(1):229-37. Epub 2009 Aug 13.
Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial.
Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, Testa L, Stecco A, Tarletti R, Miglioretti M, Fava E, Nasuelli N, Cisari C, Massara M, Vercelli R, Oggioni GD, Carriero A, Cantello R, Monaco F, Fagioli F.
Department of Neurology Eastern Piedmont University, Maggiore della Carità Hospital, 28100 Novara, Italy. mazzini.l@libero.it
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating incurable disease. Stem-cell-based therapies represent a new possible strategy for ALS clinical research. The objectives of this Phase 1 clinical study were to assess the feasibility and toxicity of mesenchymal stem cell transplantation and to test the impact of a cell therapy in ALS patients. The trial was approved and monitored by the National Institute of Health and by the Ethics Committees of all participating Institutions. Autologous MSCs were isolated from bone marrow, expanded in vitro and analyzed according to GMP conditions. Expanded MSCs were suspended in the autologous cerebrospinal fluid (CSF) and directly transplanted into the spinal cord at a high thoracic level with a surgical procedure. Ten ALS patients were enrolled and regularly monitored before and after transplantation by clinical, psychological, neuroradiological and neurophysiological assessments. There was no immediate or delayed transplant-related toxicity. Clinical, laboratory, and radiographic evaluations of the patients showed no serious transplant-related adverse events. Magnetic resonance images (MRI) showed no structural changes (including tumor formation) in either the brain or the spinal cord. However the lack of post mortem material prevents any definitive conclusion about the vitality of the MSCs after transplantation. In conclusion, this study confirms that MSC transplantation into the spinal cord of ALS patients is safe and that MSCs might have a clinical use for future ALS cell based clinical trials.
Copyright 2009 Elsevier Inc. All rights reserved.
PMID: 19682989 [PubMed – indexed for MEDLINE]

 
Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement?

CNS Neurol Disord Drug Targets. 2010 Jul;9(3):314-24.

Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement?

Silani V, Calzarossa C, Cova L, Ticozzi N.

Department of Neurology and Laboratory of Neuroscience, “Dino Ferrari” Center, Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, Milano, Italy. vincenzo@silani.com

Abstract
Given the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), compelling preclinical data on stem cell research has targeted this disease as a candidate for stem cell treatment. Stem cell transplantation has been effective in several animal models, but the underlying biological pathways of restorative processes are still unresolved. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results in preclinical animal models, in addition to replacement of lost motor neurons. The clinical target in ALS has shifted from being neuroncentered to focus on the interaction between motor neurons and non-neuronal cells (mainly astroglial or microglial). In fact, one of the fundamental unanswered questions in ALS is whether and how much motor neuron death depends on neighboring cells, and how wildtype non-neuronal cells may protect motor neurons expressing an ALS-causing mutation. Lately, motor neuron replacement has been successfully achieved in animal models with reinnervation of the muscle target. Even if many biological issues need to be solved in preclinical models, preliminary stem cell transplantation trials have been performed in ALS patients with conflicting results. The review discusses relevant topics regarding the application of stem cell research to ALS focusing on their therapeutic relevance and mechanisms of action.
PMID: 20406179 [PubMed – in process]

 
Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery.

Growth Factors. 2009 Jun;27(3):133-40.
Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery.
Lunn JS, Hefferan MP, Marsala M, Feldman EL.
Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by loss of both upper and lower motor neurons. ALS progression is complex and likely due to cellular dysfunction at multiple levels, including mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, axonal dysfunction, reactive astrocytosis, and mutant superoxide dismutase expression, therefore, treatment must provide neuronal protection from multiple insults. A significant amount of ALS research focuses on growth factor-based therapies. Growth factors including insulin-like growth factor-I, vascular endothelial growth factor, brain-derived neurotrophic factor, and glial-derived neurotrophic factor exhibit robust neuroprotective effects on motor neurons in ALS models. Issues concerning growth factor delivery, stability and unwanted side effects slow the transfer of these treatments to human ALS patients. Stem cells represent a new therapeutic approach offering both cellular replacement and trophic support for the existing population. Combination therapy consisting of stem cells expressing beneficial growth factors may provide a comprehensive treatment for ALS.
PMID: 19294549 [PubMed – indexed for MEDLINE]

 
Stem cell-derived motor neurons: applications and challenges in amyotrophic lateral sclerosis.

Curr Stem Cell Res Ther. 2009 Sep;4(3):178-99.

Stem cell-derived motor neurons: applications and challenges in amyotrophic lateral sclerosis.
Thonhoff JR, Ojeda L, Wu P.

Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-0620, USA.

Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the selective loss of both spinal and upper motor neurons. One strategy in treating ALS is to use stem cells to replace lost spinal motor neurons. However, transplanted stem cell-derived motor neurons may not survive when exposed to the harsh microenvironment in the spinal cord of ALS. In particular, dysfunctional astrocytes and overactivated microglia in ALS may limit the survival of motor neurons generated from cell replacement therapy. On the other hand, stem cells may provide large quantities of motor neurons that can be used for studying glia-mediated toxic mechanisms and potential therapies in ALS. Here we will review methods and molecular factors for directed differentiation of stem cells into spinal motor neurons, the potential uses of these models for dissecting the mechanisms underlying glia-induced motor neuron degeneration and screening for new therapeutics aimed at protecting motor neurons in ALS, as well as discuss challenges facing the development of motor neuron replacement-based cell therapies for recovery in ALS.
PMID: 19492980 [PubMed – indexed for MEDLINE]PMCID: PMC2887342Free PMC Article

 
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