Recent advances in amyotrophic lateral sclerosis

Riva, Nilo; Agosta, Federica; Lunetta, Christian; Filippi, Massimo; Quattrini, Angelo

doi:10.1007/s00415-016-8091-6

Cited by 75 publications

(50 citation statements)

References 184 publications

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“…Up-to-date analysis of the state of the current understanding of the molecular and other aspects of preclinical ALS research had been presented in a number of recent review papers (Belzil et al, 2016; Bozzoni, 2016; Clerc et al, 2016; Riva et al, 2016; Therrien et al, 2016; Zufiría et al, 2016). While genetic mutations in SOD1 gene undeniably contribute to the course of familial ALS (fALS), it is only recently that we are beginning to uncover additional factors that play a role in the etiology of sporadic ALS.…”

Section: Discussionmentioning

confidence: 99%

“…While genetic mutations in SOD1 gene undeniably contribute to the course of familial ALS (fALS), it is only recently that we are beginning to uncover additional factors that play a role in the etiology of sporadic ALS. Taking into account that only about 10% of all patients present with a fALS, with the remaining 90% of sufferers presenting with sALS (Riva et al, 2016), it is of utmost importance that novel therapeutics show clinical efficacy in sALS patient population. Furthermore, recent epidemiological evidence suggests an existing variation of ALS incidence between subcontinents that might be related to population ancestries.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

Петров

Mansfield

Moussy

et al. 2017

Front. Aging Neurosci.

368

292

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Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

Петров

Mansfield

Moussy

et al. 2017

Front. Aging Neurosci.

368

292

View full text Add to dashboard Cite

show abstract

“…Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disease, which is defined by the loss of progressive motor neurons (MNs) in the spinal cord, cerebral cortex, and brain stem. Almost 90%–95% of ALS cases are sporadic (sALS) and the remaining 5%–10% are associated with a large number of gene mutations and variants in more than 30 human chromosomal regions . The first identified familial ALS (fALS) mutation is linked to the mutant Zn/Cu superoxide dismutase (SOD1), which accounts for 20% of fALS cases .…”

Section: Introductionmentioning

confidence: 99%

A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1G93A Rats

Rehorova

Vargova

Forostyak

et al. 2019

Stem Cells Translational Medicine

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An increasing number of studies have demonstrated the beneficial effects of human mesenchymal stem cells (hMSC) in the treatment of amyotrophic lateral sclerosis (ALS). We compared the effect of repeated intrathecal applications of hMSC or their conditioned medium (CondM) using lumbar puncture or injection into the muscle ( quadriceps femoris ), or a combination of both applications in symptomatic SOD1 G93A rats. We further assessed the effect of the treatment on three major cell death pathways (necroptosis, apoptosis, and autophagy) in the spinal cord tissue. All the animals were behaviorally tested (grip strength test, Basso Beattie Bresnahan (BBB) test, and rotarod), and the tissue was analyzed immunohistochemically, by qPCR and Western blot. All symptomatic SOD1 rats treated with hMSC had a significantly increased lifespan, improved motor activity and reduced number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. Moreover, a combined hMSC delivery increased motor neuron survival, maintained neuromuscular junctions in quadriceps femoris and substantially reduced the levels of proteins involved in necroptosis (Rip1, mixed lineage kinase‐like protein, cl‐casp8), apoptosis (cl‐casp 9) and autophagy (beclin 1). Furthermore, astrogliosis and elevated levels of Connexin 43 were decreased after combined hMSC treatment. The repeated application of CondM, or intramuscular injections alone, improved motor activity; however, this improvement was not supported by changes at the molecular level. Our results provide new evidence that a combination of repeated intrathecal and intramuscular hMSC applications protects motor neurons and neuromuscular junctions, not only through a reduction of apoptosis and autophagy but also through the necroptosis pathway, which is significantly involved in cell death in rodent SOD1 G93A model of ALS. stem cells translational medicine 2019;8:535–547

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“…Amyotrophic lateral sclerosis (ALS) is the most common and severe form within the group of motor neuron diseases (MND), characterized by degeneration of both upper and lower motor neurons, leading to death two to five years after diagnosis12. While most ALS cases apparently occur sporadically (sALS), up to 10% have an affected relative and are considered familial (fALS) cases.…”

mentioning

confidence: 99%

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Riva

Clarelli

Domi

et al. 2016

Sci Rep

Self Cite

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The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies.

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Recent advances in amyotrophic lateral sclerosis

Cited by 75 publications

References 184 publications

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1G93A Rats

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

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