Cell therapy and stem cells in animal models of motor neuron disorders (original) (raw)
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REVIEW ARTILCE: Cell therapy and stem cells in animal models of motor neuron disorders
European Journal of Neuroscience, 2007
Amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (or Kennedy's disease), spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 are neurodegenerative disorders mainly affecting motor neurons and which currently lack effective therapies. Recent studies in animal models as well as primary and embryonic stem cell models of ALS, utilizing overexpression of mutated forms of Cu ⁄ Zn superoxide dismutase 1, have shown that motor neuron degeneration in these models is in part a non cell-autonomous event and that by providing genetically non-compromised supporting cells such as microglia or growth factor-excreting cells, onset can be delayed and survival increased. Using models of acute motor neuron injury it has been shown that embryonic stem cell-derived motor neurons implanted into the spinal cord can innervate muscle targets and improve functional recovery. Thus, a rationale exists for the development of cell therapies in motor neuron diseases aimed at either protecting and/or replacing lost motor neurons, interneurons as well as non-neuronal cells. This review evaluates approaches used in animal models of motor neuron disorders and their therapeutic relevance.
Cellular therapies in motor neuron diseases
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are prototypical motor neuron diseases that result in progressive weakness as a result of motor neuron dysfunction and death. Though much work has been done in both diseases to identify the cellular mechanisms of motor neuron dysfunction, once motor neurons have died, one of potential therapies to restore function would be through the use of cellular transplantation. In this review, we discuss potential strategies whereby cellular therapies, including the use of stem cells, neural progenitors and cells engineered to secrete trophic factors, may be used in motor neuron diseases. We review pre-clinical data in rodents with each of these approaches and discuss advances and regulatory issues regarding the use of cellular therapies in human motor neuron diseases.
Stem Cell Therapy in Motor Neuron Disease
Novel Aspects on Motor Neuron Disease [Working Title], 2019
Motor neuron disease (MND) is an insidious, fatal disorder that progresses with the selective loss of anterior horn cells of the spinal column. Over 150 years since it was first described, various therapeutic approaches have been tested in the quest of a cure but with little success. Current standard therapy only improves lifespan by a few months; palliative care is the only option available for patients. Stem cell therapy is a potent approach for the treatment of this devastating disease. A multitude of vitalizing effects, both paracrine and somatic, a robust safety profile, as well as ease of availability make a strong case for using these cells for therapeutic purposes. Coupled with rigorous rehabilitation, this powerful treatment modality has been shown to slow disease progression, improve quality of life, and increase survival, along with being well tolerated by amyotrophic lateral sclerosis (ALS)/ MND patients. Compelling preclinical as well as clinical evidence abounds that stem cells hold great potential as a therapy for ALS/MND. Although not a definitive solution yet, stem cells have been verified to have slowed and/or halted disease progression in a subset of ALS/MND patients.
Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement?
CNS &# 38; …, 2010
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.
Stem cell technology for the study and treatment of motor neuron diseases
Regenerative medicine, 2011
Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurolog...
Cell Transplantation, 2009
Embryonic stem (ES) cells can be induced to differentiate into motor neurons (MN). Animal models resembling MN degeneration and paralysis observed in familial amyotrophic lateral sclerosis (ALS) have been previously reported. In this work, we aimed to investigate whether transplanted MN could prevent motor deterioration in transgenic rats expressing a mutant form of human superoxide dismutase 1 (hSOD1G93A) associated with inherited ALS. Mouse ES cells were differentiated to neurons that express green fluorescent protein (GFP) under the promoter of the MN-specific gene hb9, as well as molecular markers indicative of MN identity. Cells were grafted into the lumbar spinal cord of adult wild-type (WT) or hSOD1G93A rats at 10 weeks of age, when transgenic animals are presymptomatic. Grafted cells with MN phenotype can survive for at least 1 week in hSOD1G93A animals. To quantitatively evaluate motor performance of WT and transgenic rats, we carried out weekly rotarod tests starting when ...
Stem-cell therapy for amyotrophic lateral sclerosis
Lancet
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