scholarly journals Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Sibylle Jablonka ◽  
Luisa Hennlein ◽  
Michael Sendtner
Keyword(s):  
Alzheimer’S Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Spinal Muscular Atrophy ◽  
Neurodegenerative Disorders ◽  
Muscular Atrophy ◽  
Mrna Splicing ◽  
Muscular Dystrophies ◽  
Gene Therapies ◽  
Therapy Development ◽  
Lateral Sclerosis

Abstract Background Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration. Main body Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders. Conclusion RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson’s and Alzheimer’s disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.

scholarly journals Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)

2018 ◽  
Vol 8 (12) ◽  
pp. 212 ◽  
Author(s):  
Darija Šoltić ◽  
Melissa Bowerman ◽  
Joanne Stock ◽  
Hannah Shorrock ◽  
Thomas Gillingwater ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Spinal Muscular Atrophy ◽  
Calcium Binding ◽  
Bioinformatics Analysis ◽  
Muscular Atrophy ◽  
Molecular Pathways ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Therapeutic Development ◽  
Lateral Sclerosis

Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport—both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases.

scholarly journals Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective

2017 ◽  
Vol 141 (1) ◽  
pp. 12-30 ◽  
Author(s):  
Margarida Gama-Carvalho ◽  
Marina L. Garcia-Vaquero ◽  
Francisco R. Pinto ◽  
Florence Besse ◽  
Joachim Weis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Lateral Sclerosis

scholarly journals Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development

2018 ◽  
Vol 61 (11) ◽  
pp. 685-698 ◽  
Author(s):  
Melissa Bowerman ◽  
Lyndsay M. Murray ◽  
Frédérique Scamps ◽  
Bernard L. Schneider ◽  
Rashmi Kothary ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Therapeutic Development ◽  
Lateral Sclerosis

Mitochondria and Neurodegeneration

2007 ◽  
Vol 27 (1-3) ◽  
pp. 87-104 ◽  
Author(s):  
Lucia Petrozzi ◽  
Giulia Ricci ◽  
Noemi J. Giglioli ◽  
Gabriele Siciliano ◽  
Michelangelo Mancuso
Keyword(s):  
Alzheimer’S Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Huntington's Disease ◽  
Neurodegenerative Disorders ◽  
Molecular Abnormalities ◽  
Lateral Sclerosis ◽  
Lines Of Evidence

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.

scholarly journals Examining the Relationship between Concussion and Neurodegenerative Disorders: A Review on Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD)

2021 ◽  
Author(s):  
Edward Poluyi ◽  
Eghosa Morgan ◽  
Charles Poluyi ◽  
Chibuikem Ikwuegbuenyi ◽  
Grace Imaguezegie
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Brain Injuries ◽  
Tau Proteins ◽  
Glutamate Excitotoxicity ◽  
Clinical Test ◽  
Lateral Sclerosis

Abstract Background Current epidemiological studies have examined the associations between moderate and severe traumatic brain injury (TBI) and their risks of developing neurodegenerative diseases. Concussion, also known as mild TBI (mTBI), is however quite distinct from moderate or severe TBIs. Only few studies in this burgeoning area have examined concussion—especially repetitive episodes—and neurodegenerative diseases. Thus, no definite relationship has been established between them. Objectives This review will discuss the available literatures linking concussion and amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Materials and Methods Given the complexity of this subject, a realist review methodology was selected which includes clarifying the scope and developing a theoretical framework, developing a search strategy, selection and appraisal, data extraction, and synthesis. A detailed literature matrix was set out in order to get relevant and recent findings on this topic. Results Presently, there is no objective clinical test for the diagnosis of concussion because the features are less obvious on physical examination. Absence of an objective test in diagnosing concussion sometimes leads to skepticism when confirming the presence or absence of concussion. Intriguingly, several possible explanations have been proposed in the pathological mechanisms that lead to the development of some neurodegenerative disorders (such as ALS and AD) and concussion but the two major events are deposition of tau proteins (abnormal microtubule proteins) and neuroinflammation, which ranges from glutamate excitotoxicity pathways and inflammatory pathways (which leads to a rise in the metabolic demands of microglia cells and neurons), to mitochondrial function via the oxidative pathways. Conclusion mTBI constitutes majority of brain injuries. However, studies have focused mostly on moderate-to-severe TBI as highlighted above with inconclusive and paucity of studies linking concussion and neurodegenerative disorders. Although, it is highly probable that repetitive concussion (mTBI) and subconcussive head injuries may be risk factors for ALS) and AD from this review. It will be imperative therefore to conduct more research with a focus on mTBI and its association with ALS and AD.

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