scholarly journals Lessons Learned From Translational Research in Neuromuscular Diseases: Impact on Study Design, Outcome Measures and Managing Expectation

2021 ◽  
Vol 12 ◽  
Author(s):  
Georgia Stimpson ◽  
Mary Chesshyre ◽  
Giovanni Baranello ◽  
Francesco Muntoni
Keyword(s):  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Clinical Work ◽  
Lessons Learned ◽  
Preclinical Research ◽  
Innovative Therapy ◽  
Innovative Methods ◽  
Trial Endpoints ◽  
Matching Criteria

Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues.

scholarly journals CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1522
Author(s):  
Karsten Krause ◽  
Maximilian Wulf ◽  
Paula Sommer ◽  
Katalin Barkovits ◽  
Matthias Vorgerd ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Neuromuscular Disorders ◽  
Disease Onset ◽  
Neuromuscular Diseases ◽  
Promising Alternative ◽  
Alternative Techniques ◽  
Subordinate Role ◽  
Lateral Sclerosis

Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.

scholarly journals Obstetric-Gynecological Complications in Neuromuscular Disorders

2020 ◽  
Vol 1 (3) ◽  
pp. 5-8
Author(s):  
Lakshmi Digala ◽  
Zahra Haider ◽  
Raghav Govindarajan
Keyword(s):  
Neuromuscular Disease ◽  
Muscular Atrophy ◽  
Case Reports ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Retrospective Chart Review ◽  
Obstetric Complications ◽  
University Of Missouri ◽  
Charcot Marie Tooth Disease ◽  
One Year

Background and Objective: The data on the obstetric and gynecological complications in patients diagnosed with neuromuscular diseases is very limited and is primarily obtained from various case reports, series, and small studies.  The objective of our study was to analyze the prevalence of these complications in a large cohort of patients with various neuromuscular diseases. Methods: This study is a retrospective chart review of patients diagnosed with various neuromuscular diseases at the University of Missouri, Columbia, from 2012 to 2017. We included patients who have at least one year follow up with us. We collected data on patient demographics, neuromuscular disease diagnosed, obstetric complications, and gynecologic complications. Data are reported as means ± SEM, and the results reported using prevalence rates. Results: Ninety-five female patients were identified. Among them, 97% were Caucasian, and 3% were African-American with a mean age of 47.96 years.  Neuromuscular diseases identified among them are Myasthenia Gravis (44%), Muscular Dystrophy (23%), Amyotrophic Lateral Sclerosis-ALS (16%), Charcot-Marie-Tooth disease-CMT (10%), and Spinal Muscular atrophy- SMA (7%). The majority of the patients reviewed have had no obstetric complications- (89.40%). The most common obstetric complication recorded was C-section (8.40%).  41% of women did not have any gynecological complaints. Urine incontinence (24.20%) is the most common complication. Conclusion: C-sections and urinary incontinence are common obstetric and gynecological events seen in women with neuromuscular disease.

scholarly journals Assessing Cognitive Function in Neuromuscular Diseases: A Pilot Study in a Sample of Children and Adolescents

2021 ◽  
Vol 10 (20) ◽  
pp. 4777
Author(s):  
Rossella D’Alessandro ◽  
Neftj Ragusa ◽  
Martina Vacchetti ◽  
Enrica Rolle ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Motor Impairment ◽  
Sensory Neuropathy ◽  
Becker Muscular Dystrophy ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Cross Sectional

Central nervous system (CNS) involvement has been variously studied in pediatric neuromuscular disorders (NMDs). The primary goal of this study was to assess cognitive functioning in NMDs, and secondary aims were to investigate possible associations of cognitive impairment with motor impairment, neurodevelopmental delay, and genotype. This was a cross-sectional study of 43 pediatric patients, affected by six NMDs. Myotonic dystrophy type 1 (DM1) and glycogen storage disease type 2 (GSD2) patients had a delay on the Bayley-III scales. On Wechsler scales, DMD and DM1 patients showed lower FSIQ scores, with an intellectual disability (ID) in 27% and 50%, respectively. FSIQ was normal in Becker muscular dystrophy (BMD), GSD2, and hereditary motor sensory neuropathy (HMSN) patients, while higher individual scores were found in the spinal muscular atrophy (SMA) group. In the DM1 cohort, lower FSIQ correlated with worse motor performance (ρ = 0.84, p < 0.05), and delayed speech acquisition was associated with ID (p = 0.048), with worse cognitive impairment in the congenital than in the infantile form (p = 0.04). This study provides further evidence of CNS in some NMDs and reinforces the need to include cognitive assessment in protocols of care of selected pediatric NMDs.

scholarly journals Genetic approaches to the treatment of inherited neuromuscular diseases

2019 ◽  
Vol 28 (R1) ◽  
pp. R55-R64 ◽  
Author(s):  
Bhavya Ravi ◽  
Anthony Antonellis ◽  
Charlotte J Sumner ◽  
Andrew P Lieberman
Keyword(s):  
Motor Neurons ◽  
Viral Vectors ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Clinical Severity ◽  
Charcot Marie Tooth Disease ◽  
Degenerative Disorders ◽  
Clinical Benefits

Abstract Inherited neuromuscular diseases are a heterogeneous group of developmental and degenerative disorders that affect motor unit function. Major challenges toward developing therapies for these diseases include heterogeneity with respect to clinical severity, age of onset and the primary cell type that is affected (e.g. motor neurons, skeletal muscle and Schwann cells). Here, we review recent progress toward the establishment of genetic therapies to treat inherited neuromuscular disorders that affect both children and adults with a focus on spinal muscular atrophy, Charcot–Marie–Tooth disease and spinal and bulbar muscular atrophy. We discuss clinical features, causative mutations and emerging approaches that are undergoing testing in preclinical models and in patients or that have received recent approval for clinical use. Many of these efforts employ antisense oligonucleotides to alter pre-mRNA splicing or diminish target gene expression and use viral vectors to replace expression of mutant genes. Finally, we discuss remaining challenges for optimizing the delivery and effectiveness of these approaches. In sum, therapeutic strategies for neuromuscular diseases have shown encouraging results, raising hope that recent strides will translate into significant clinical benefits for patients with these disorders.

scholarly journals Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

2020 ◽  
Vol 21 (24) ◽  
pp. 9589
Author(s):  
Wei Chiu ◽  
Ya-Hsin Hsun ◽  
Kao-Jung Chang ◽  
Aliaksandr A. Yarmishyn ◽  
Yu-Jer Hsiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Premature Termination Codon ◽  
Becker Muscular Dystrophy ◽  
Functional Impairments ◽  
Motor Neuron Diseases

Neuromuscular diseases (NMDs) belong to a class of functional impairments that cause dysfunctions of the motor neuron-muscle functional axis components. Inherited monogenic neuromuscular disorders encompass both muscular dystrophies and motor neuron diseases. Understanding of their causative genetic defects and pathological genetic mechanisms has led to the unprecedented clinical translation of genetic therapies. Challenged by a broad range of gene defect types, researchers have developed different approaches to tackle mutations by hijacking the cellular gene expression machinery to minimize the mutational damage and produce the functional target proteins. Such manipulations may be directed to any point of the gene expression axis, such as classical gene augmentation, modulating premature termination codon ribosomal bypass, splicing modification of pre-mRNA, etc. With the soar of the CRISPR-based gene editing systems, researchers now gravitate toward genome surgery in tackling NMDs by directly correcting the mutational defects at the genome level and expanding the scope of targetable NMDs. In this article, we will review the current development of gene therapy and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophy Type 2C (LGMD2C).

scholarly journals Neuromuscular disease - Gene transfer for children

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Matthew Martin ◽  
Margie Ream ◽  
Nancy Kuntz ◽  
Katherine Mathews ◽  
Anne Connolly
Keyword(s):  
Gene Transfer ◽  
Liver Dysfunction ◽  
Viral Vectors ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Population Level ◽  
Clinical Work ◽  
Great Promise ◽  
Duchene Muscular Dystrophy ◽  
Early Timing

Successful gene transfer therapy (GTT) provides a functional copy of a gene to appropriate tissues for affected patients. While technically difficult, GTT holds great promise for treating and even curing previously fatal diseases. GTT for Spinal Muscular Atrophy is available commercially and ongoing studies continue to show it is safe and effective. Subclinical liver dysfunction is more common in older, heavier children receiving higher vial loads. Human trials support preclinical studies showing early timing of therapy is important. GTT for Duchene Muscular Dystrophy has required strategic approaches to create mini- and micro-dystrophin genes that will fit into available viral vectors. There are multiple ongoing studies that overall demonstrate good safety and efficacy. GTT for X-Linked Myotubular Myopathy is being studied in an ongoing trial that has shown improvement in respiratory function (including ventilator independence), neuromuscular function, and histopathological evaluation. Three patients with severe cholestatic liver dysfunction have died. Evaluation is ongoing to better understand these events. While GTT for neuromuscular disorders holds significant promise, it is not without risks and requires in-depth knowledge of the disease, abundant pre-clinical work, careful patient education, and ongoing patient care. There are a number of key questions that must be considered regarding the feasibility of expanding GTT to new disorders These examples illustrate how advances in GTT benefit children on a population level and may themselves benefit from early detection by NBS. By becoming involved in advocacy at state and federal levels, families and physicians can impact newborn screening policy and implementation regarding these disorders.

C. elegans models of neuromuscular diseases expedite translational research

2010 ◽  
Vol 1 (3) ◽  
Author(s):  
James Sleigh ◽  
David Sattelle
Keyword(s):  
Large Scale ◽  
Genetic Model ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Model Organism ◽  
Disease Genes ◽  
Chemical Library ◽  
C Elegans

AbstractThe nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

scholarly journals Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ambrosini ◽  
Danila Baldessari ◽  
Silvia Pozzi ◽  
Manuela Battaglia ◽  
Elena Beltrami ◽  
...  
Keyword(s):  
Neuromuscular Disorders ◽  
Healthcare Research ◽  
Lessons Learned ◽  
Patient Organisation ◽  
Delivery Of Care ◽  
Innovative Therapy ◽  
Disease Research ◽  
Strategic Initiative ◽  
Grant Applications ◽  
Funding Program

AbstractIn 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

scholarly journals Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001)

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Takashi Nakajima ◽  
Yoshiyuki Sankai ◽  
Shinjiro Takata ◽  
Yoko Kobayashi ◽  
Yoshihito Ando ◽  
...  
Keyword(s):  
Crossover Trial ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Walk Test ◽  
Efficacy And Safety ◽  
Muscle Testing ◽  
Ambulatory Ability ◽  
Secondary Endpoints ◽  
Randomised Controlled ◽  
Hybrid Assistive Limb

Abstract Background Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. Results We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667–19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. Conclusions HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. Trial registration: JMACTR, JMA-IIA00156

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