scholarly journals Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model

2020 ◽  
Vol 48 (6) ◽  
pp. 2853-2865 ◽  
Author(s):  
Lei Sheng ◽  
Frank Rigo ◽  
C Frank Bennett ◽  
Adrian R Krainer ◽  
Yimin Hua
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Time Course ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Body Weight Gain ◽  
Target Sequence ◽  
Advantages And Disadvantages ◽  
Extended Target ◽  
The Central Nervous System

Abstract Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, a splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2′-O-methoxyethyl (MOE) with a phosphorothioate backbone and morpholino with a phosphorodiamidate backbone—with the same or extended target sequence as nusinersen—displayed efficient rescue of SMA mouse models. Here, we compared the therapeutic efficacy of these two modification chemistries in rescue of a severe mouse model using ASO10-29—a 2-nt longer version of nusinersen—via subcutaneous injection. Although both chemistries efficiently corrected SMN2 splicing in various tissues, restored motor function and improved the integrity of neuromuscular junctions, MOE-modified ASO10-29 (MOE10-29) was more efficacious than morpholino-modified ASO10-29 (PMO10-29) at the same molar dose, as seen by longer survival, greater body-weight gain and better preservation of motor neurons. Time-course analysis revealed that MOE10-29 had more persistent effects than PMO10-29. On the other hand, PMO10-29 appears to more readily cross an immature blood-brain barrier following systemic administration, showing more robust initial effects on SMN2 exon 7 inclusion, but less persistence in the central nervous system. We conclude that both modifications can be effective as splice-switching ASOs in the context of SMA and potentially other diseases, and discuss the advantages and disadvantages of each.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

scholarly journals Arthrogryposis multiplex congenita in Aberdeen Angus cattle in Uruguay

2020 ◽  
Vol 40 (6) ◽  
pp. 426-429
Author(s):  
Agustín Romero ◽  
Carolina Briano ◽  
Fernando Dutra Quintela
Keyword(s):  
Motor Neurons ◽  
Peripheral Nerves ◽  
Dna Analysis ◽  
Muscular Atrophy ◽  
Size Variation ◽  
Arthrogryposis Multiplex Congenita ◽  
Angus Cattle ◽  
Fiber Size ◽  
The Central Nervous System ◽  
First Time

ABSTRACT: Arthrogryposis multiplex congenita is reported for the first time in the Aberdeen Angus (AA) breed in Uruguay. In a commercial herd of 30 purebred Aberdeen Angus cows, two calves with severe musculoskeletal malformations died at birth. The cows had been inseminated using semen imported from Argentina from one elite AA sire only. At necropsy, one calf showed severe muscular atrophy, arthrogryposis affecting all four limbs and the spine, kyphoscoliosis and torticollis. Histopathology showed muscular atrophy with marked fiber size variation and abundant fibroadipose fibers. The central nervous system only showed congestion and edema due to dystocia, whereas the peripheral nerves and the number of motor neurons in the spinal appeared normal. DNA analysis confirmed arthrogryposis multiplex congenita. It is concluded that disease in Aberdeen Angus cattle is due to failure in the neuromuscular junction.

scholarly journals Morphological Characteristics of Motor Neurons Do Not Determine Their Relative Susceptibility to Degeneration in a Mouse Model of Severe Spinal Muscular Atrophy

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52605 ◽  
Author(s):  
Sophie R. Thomson ◽  
Joya E. Nahon ◽  
Chantal A. Mutsaers ◽  
Derek Thomson ◽  
Gillian Hamilton ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Morphological Characteristics ◽  
Relative Susceptibility

scholarly journals Electrophysiological Properties of Motor Neurons in a Mouse Model of Severe Spinal Muscular Atrophy: In Vitro versus In Vivo Development

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11696 ◽  
Author(s):  
Hongmei Zhang ◽  
Natallia Robinson ◽  
Chiayen Wu ◽  
Wenlan Wang ◽  
Melissa A. Harrington
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Electrophysiological Properties

scholarly journals Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy

2021 ◽  
Author(s):  
Federica Fulceri ◽  
Francesca Biagioni ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Larisa Ryskalin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Muscle Spindles ◽  
Neuromuscular Disorder ◽  
Type Iii ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.

scholarly journals Cortical hyperexcitability drives dying forward ALS symptoms and pathology in mice

2021 ◽  
Author(s):  
Mouna Haidar ◽  
Aida Viden ◽  
Brittany Cuic ◽  
Taide Wang ◽  
Marius Rosier ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Corticospinal Tract ◽  
Neuromuscular Junctions ◽  
Dna Binding Protein ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Cortical Hyperexcitability ◽  
The Central Nervous System ◽  
Lateral Sclerosis ◽  
Intrinsic Feature

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder caused by degeneration of motor neurons in the cortex and spinal cord. The origin of ALS in the central nervous system is unclear, however cortical hyperexcitability appears as an early and intrinsic feature of ALS and has been linked to degeneration of spinal motor neurons via a dying-forward mechanism. Here, we implement chemogenetics to validate the dying forward hypothesis of ALS in mice. We show that chronic hyperexcitability of corticomotoneurons induced by excitatory chemogenetics results in motor symptoms and core neuropathological hallmarks of ALS, including corticomotoneuron loss, corticospinal tract degeneration and reactive gliosis. Importantly, corticomotoneuron loss was sufficient to drive degeneration of spinal motor neurons and neuromuscular junctions (NMJs), associated with cytoplasmic TAR DNA binding protein 43 (TDP-43) pathology. These findings establish a cortical origin of ALS mediated by neuronal hyperexcitability, consistent with a dying forward mechanism of neurodegeneration.

scholarly journals Assessment of motor neuron pathology and potential compensatory mechanisms in phenotypically normal mice with reduced Survival Motor Neuron levels.

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Rebecca Xu Xu ◽  
Lyndsay M. Murray M. Murray Murray ◽  
Yves De Repentigny De Repentigny ◽  
Rashmi Kothary Kothary
Keyword(s):  
Motor Neuron ◽  
Mouse Models ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Compensatory Mechanisms ◽  
Protein Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a destructive pediatric neuromuscular disorder caused by low survival motor neuron (Smn) protein levels due to mutations and deletions within the survival motor neuron 1 (SMN1) gene. Motor neurons are the main pathological targets, and along with neuromuscular junctions (NMJs), they play an early significant role in the pathogenesis of SMA. Previous studies demonstrate that a pathological reduction in Smn levels can lead to significant remodeling defects in both the outgrowth of axonal sprouts and in the nerve-directed clustering of AChRs in mouse models. However, whether this pathological reduction in Smn leads to ubclinical features has not been investigated. Here, we have employed the Smn2B/2B and Smn+/- mouse models to study whether similar SMA pathology is present sub-clinically, and if so whether there is any compensation present. We show a decrease in the motor neuron number in the mouse models, no change in myelin thickness and modest NMJ pathology in both mouse models. Additionally, compensation through the expansion of the motor unit size is suggested.L’amyotrophie spinale (AMS) est un trouble neuromusculaire pédiatrique destructif causé par le niveau bas de protéine du neurone de moteur de survie (NMS) en raison des mutations et des effacements dans le neurone de moteur de survie 1 gène (NMS1). Des neurones du moteur sont les cibles pathologiques principales, et ce, avec des jonctions neuromusculaires (JNMs), ils jouent, en avance, un rôle significatif dans la pathogénie de AMS. Des études précédentes démontrent qu’une réduction pathologique de niveaux de NMS peut mener aux défauts importants de réorganisation tant dans l’excroissance axonale que dans l’agrégation du récepteur de l’acétylcholine (AChR) sous la terminaison nerveuse dans des modèles de souris. Cependant, si cette reduction pathologique de NMS mène aux caractéristiques infracliniques n’a pas été à l’étude. Ici, nous avons employé le NMS2B/2B et NMS +/- des modèles de souris afin de déterminer si une pathologie semblable à l’AMS est présente infracliniquement, ainsi s’il y a présence de quelconque compensation. Nous montrons une diminution dans le nombre des neurones du moteur dans les modèles de souris, aucun changement de l’épaisseur du myelin et une pathologie modeste de JNM dans les deux modèles de souris. De plus, une compensation par l’expansion de la taille d’unité du moteur est suggérée.

Weakness

2018 ◽  
Author(s):  
Cris S. Constantinescu ◽  
Su-Yin Lim
Keyword(s):  
Muscle Weakness ◽  
Motor Neurons ◽  
Neurological Examination ◽  
Peripheral Nerves ◽  
Time Course ◽  
Neuromuscular Junctions ◽  
Systemic Disease ◽  
Neuromuscular Disorder ◽  
Nerve Roots ◽  
Upper Motor Neurons

Muscle weakness may reflect systemic disease (such as sepsis or severe hypokalaemia) or a neuromuscular disorder. The origin of neuromuscular weakness may be localized to upper motor neurons, lower motor neurons (including nerve roots, plexus, and peripheral nerves), anterior horn cells, neuromuscular junctions, or muscles. The mode of onset of weakness, its time course, and the findings on general and neurological examination will usually differentiate between the possible diagnoses. The approach to the patient with suspected neuromuscular weakness is described in this chapter.

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