scholarly journals Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 20 (11) ◽  
pp. 2616 ◽  
Author(s):  
Natalia Nowicka ◽  
Jakub Juranek ◽  
Judyta K. Juranek ◽  
Joanna Wojtkiewicz
Keyword(s):  
Risk Factors ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Sod1 Gene ◽  
Stem Cell Therapies ◽  
Cell Therapies ◽  
Emerging Therapies ◽  
Emerging Treatments ◽  
Phase Ii And Iii ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials.

scholarly journals A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiaojiao Xu ◽  
Dingding Shen ◽  
Yining Gao ◽  
Qinming Zhou ◽  
You Ni ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Critical Role ◽  
Cell Therapies ◽  
Gene Therapies ◽  
Open Questions ◽  
Novel Therapeutic Strategies ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis

2008 ◽  
Vol 36 (6) ◽  
pp. 1322-1328 ◽  
Author(s):  
Willianne I.M. Vonk ◽  
Leo W.J. Klomp
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Transition Metals ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Sod1 Gene ◽  
Brain And Spinal Cord ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for ALS.

scholarly journals Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation

2021 ◽  
Vol 22 (4) ◽  
pp. 1796
Author(s):  
Audrey Dangoumau ◽  
Sylviane Marouillat ◽  
Roxane Coelho ◽  
François Wurmser ◽  
Céline Brulard ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Genetic Alterations ◽  
Sod1 Gene ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Vitro Model ◽  
Lateral Sclerosis

Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.

scholarly journals What causes amyotrophic lateral sclerosis?

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 371 ◽  
Author(s):  
Sarah Martin ◽  
Ahmad Al Khleifat ◽  
Ammar Al-Chalabi
Keyword(s):  
Risk Factors ◽  
Amyotrophic Lateral Sclerosis ◽  
Respiratory Failure ◽  
Neurodegenerative Disease ◽  
Motor Neurons ◽  
Environmental Risk ◽  
Age Of Onset ◽  
Genetic Associations ◽  
Male Predominance ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.

scholarly journals Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis

1998 ◽  
Vol 25 (3) ◽  
pp. 192-196 ◽  
Author(s):  
Y. Boukaftane ◽  
J. Khoris ◽  
B. Moulard ◽  
F. Salachas ◽  
V. Meininger ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Binding Sites ◽  
Autosomal Dominant ◽  
Gene Mutations ◽  
Premature Death ◽  
Sod1 Gene ◽  
Autosomal Dominant Trait ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

ABSTRACT:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.

scholarly journals Emerging therapies for amyotrophic lateral sclerosis applied to drug discovery

2021 ◽  
Author(s):  
Pedro José Honório de Albuquerque ◽  
Laura Guerra Lopes ◽  
Jordy Silva de Carvalho ◽  
Luzilene Pereira de Lima ◽  
Marina Galdino da Rocha Pitta
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Kinase Inhibitors ◽  
Genetic Disorders ◽  
Human Monoclonal Antibody ◽  
Clinical Intervention ◽  
Definitive Treatment ◽  
Emerging Therapies ◽  
Pubmed Database ◽  
Lateral Sclerosis

Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease mainly caused by genetic disorders. This progressive disorder involves the degeneration of motor neurons at various levels. Drugs have been studied, and they show improvement in survival and reduced progression of the disease, they are riluzole and edaravone. Objectives: Investigate emerging therapies for the treatment of ALS. Methods: The Pubmed database was used to conduct the research, and the keywords were “Amyotrophic Lateral Sclerosis”, “Emerging”, “Therapies”,”Drugs”, all present in Mesh. Articles from 2016 to 2021 were used. And the survey was conducted on May 2, 2021. Results: Only two drugs have been approved yet by the Food and Drug Administration for the treatment of ALS, riluzole and edaravone, and each one offers modest benefits in mortality and/or function. On the other hand, 88 studies of clinical intervention trials are active using different drugs. Current therapies under development include oral tyrosine kinase inhibitors (masitinib, trametinib); the antisense oligonucleotide (tofersen); the human monoclonal antibody inhibitor (ravulizumab); and mesenchymal stem cells (MSC); among others (RT001, Enoxacin, Engensis, ANX005, Deferiprone). Conclusions: Due to gaps in the knowledge of the specific pathophysiology of ALS, the definitive treatment is still a mystery. The drugs currently in use, riluzole and edaravone, are the most promising in terms of delaying the progression of the disease.

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