scholarly journals Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back

2020 ◽  
Vol 10 (4) ◽  
pp. 258
Author(s):  
Laurine Buscara ◽  
David-Alexandre Gross ◽  
Nathalie Daniele
Keyword(s):  
Clinical Trials ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Whole Body ◽  
Skeletal Muscle Atrophy ◽  
General Strategy ◽  
Serious Adverse Events ◽  
Worst Case ◽  
Organ Failures

Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed.

scholarly journals Treatment with nusinersen in a girl with spinal muscular atrophy type 1 - Case report

2020 ◽  
Vol 89 (5-6) ◽  
pp. 320-326
Author(s):  
Tanja Loboda ◽  
Tita Butenko ◽  
Tanja Golli ◽  
Damjan Osredkar
Keyword(s):  
Spinal Muscular Atrophy ◽  
Respiratory Infections ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Natural Course ◽  
Dramatic Improvement ◽  
Serious Adverse Events ◽  
Spinal Muscular Atrophy Type

We report the case of a girl with spinal muscular atrophy (SMA) type 1, who is the first patient with SMA in Slovenia treated with nusinersen, the first disease modifying therapy available for these patients. SMA is an autosomal recessive neuromuscular disorder characterized by muscle weakness, atrophy and paralysis due to the degeneration of the anterior horn cells, leading to premature death, most commonly due to respiratory infections. Nusinersen, an antisense oligonucleotide, was clinically approved based on clinical trials showing dramatic improvement in the natural course of infantile-onset SMA. After the genetic confirmation of SMA, our girl was the first child in Slovenia to receive nusinersen, which was provided through an expanded access programme. She received intrathecal applications of nusinersen according to the protocol. No serious adverse events were observed. Assessment of her motor skills was performed using The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP – INTEND) before the beginning of treatment and after completing the first 7 applications of nusinersen. She scored 21/64 points before the introduction of treatment and 32/64 after the completion of treatment. In conclusion, nusinersen improved the CHOP – INTEND motor function score and has been effective in delaying the expected natural course of SMA in our patient.

scholarly journals Gene therapy for spinal muscular atrophy: the Qatari experience

Gene Therapy ◽  
2021 ◽  
Author(s):  
Hossamaldein Gaber Ali ◽  
Khalid Ibrahim ◽  
Mahmoud Fawzi Elsaid ◽  
Reem Babiker Mohamed ◽  
Mahmoud I. A. Abeidah ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Troponin I ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Progressive Muscle Weakness ◽  
Elevated Bilirubin

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

scholarly journals The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement

2020 ◽  
Vol 21 (17) ◽  
pp. 6429 ◽  
Author(s):  
Sara Bachiller ◽  
Isabel M. Alonso-Bellido ◽  
Luis Miguel Real ◽  
Eva María Pérez-Villegas ◽  
José Luis Venero ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Ubiquitin Proteasome System ◽  
Neuromuscular Disorder ◽  
Enzymatic Reactions ◽  
Protein Homeostasis ◽  
Motor Neuron Diseases ◽  
Charcot Marie Tooth Disease ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome

Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin–proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin–protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.

Neuromuscular Disorders Presenting as Congenital Bilateral Vocal Cord Paralysis

2001 ◽  
Vol 110 (10) ◽  
pp. 952-955 ◽  
Author(s):  
Jose F. Lapeña ◽  
Robert G. Berkowitz
Keyword(s):  
Vocal Cord ◽  
Positive Airway Pressure ◽  
Vocal Cord Paralysis ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Upper Airway ◽  
Neuromuscular Disorder ◽  
Bilateral Vocal Cord Paralysis ◽  
Neuromuscular Dysfunction ◽  
Congenital Myasthenia

Congenital bilateral vocal cord paralysis (BVCP) can be associated with an underlying neuromuscular disorder, and may present before other features of the neuromuscular disorder become apparent. All infants less than 12 months of age presenting with BVCP between July 1987 and July 1999 at the Royal Children's Hospital, Melbourne, in whom a neuromuscular disorder was subsequently diagnosed were followed. Three children in whom BVCP was diagnosed soon after birth and before recognition of an underlying neuromuscular disorder were identified. All presented with upper airway obstructive symptoms at birth, had a diagnosis of bilateral abductor vocal cord paralysis made at awake flexible laryngoscopy, and had no underlying structural laryngeal abnormality on microlaryngoscopy and bronchoscopy. Two children required a tracheostomy, and 1 child was weaned from nasopharyngeal continuous positive airway pressure after 3 weeks. Subsequent neuromuscular symptoms were recognized between 4 months and 7 years later, leading to diagnoses of facioscapulohumeral myopathy, spinal muscular atrophy, and congenital myasthenia gravis. In each case, the prognosis for recovery from symptoms related to BVCP reflected that of the underlying neuromuscular disorder. This experience suggests that congenital BVCP may be a feature of an unrecognized neuromuscular condition. This possibility should be considered particularly in the presence of associated neurodevelopmental or neuromuscular dysfunction, or in cases in which BVCP is progressive.

scholarly journals The therapeutic effect and safety of the drugs for COVID-19: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Rong Qiu ◽  
Jingwei Li ◽  
Yuxuan Xiao ◽  
Ziyi Gao ◽  
Yihang Weng ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Clinical Improvement ◽  
Discharge Rate ◽  
Whole Body ◽  
Cochrane Library ◽  
Control Group ◽  
Serious Adverse Events ◽  
Improvement Rate ◽  
Great Loss

Abstract Background: Coronavirus disease 2019 (COVID-19) has spread almost all regions of the world and caused great loss to the whole body of mankind. Thus, numerous clinical trials were conducted to find specific medicine for COVID-19 recently. However, it remains unanswered whether they are beneficial. Objective: This study aimed to evaluate the efficiency and safety of the COVID-19 medicine. Methods: Studies were determined through searching PubMed, Embase, Cochrane Library and Medline. The clinical trials of COVID-19 medicine were involved with eligible end points containing mortality, discharge rate, rate of clinical improvement and rate of serious adverse events. The risk ratio (RR) was adopted for variables as effect magnitude with 95% confidence intervals (CI), and the random‐effects model was adopted for analysis. Results: A total of eleven RCTs and eleven Non-RCTs involving 12,796 patients were included in our study, whose intervening measures contained three major types of COVID-19 medicine, ACEI/ARB, antiviral medicine and chloroquine/hydroxychloroquine. Compared to control group, COVID-19 medicine has the obvious advantage in reducing discharge rate (RR, 1.18; 95% CI, 1.07-1.29, p<0. 05) and clinical improvement rate (RR, 1.15; 95% CI, 1.05-1.26, p<0. 05), no distinct effect on mortality (RR, 0.79; 95% CI, 0.53-1.17, p=0. 24). In addition, the serious adverse events rate (RR, 0.74; 95% CI, 0.62-0.88, p<0. 05) of COVID-19 medicine is lower than control group. Among different types of medicine, significant benefits in lowering the mortality seem to only occur in antiviral medicine. Conclusion: The results indicated antiviral medicine was potential drug of first choice recommended for COVID-19 treatment. Chloroquine/hydroxychloroquine therapy was not recommended for COVID-19 patients. Additionally, the ACEI/ARB could be adopted for COVID-19 treatment when combined with standard treatment.

scholarly journals Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy

2019 ◽  
Vol 24 (3) ◽  
pp. 194-203 ◽  
Author(s):  
Erin E. Neil ◽  
Elizabeth K. Bisaccia
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotide ◽  
Rna Splicing ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Insurance Coverage ◽  
Survival Motor Neuron ◽  
Duration Of Treatment ◽  
Treatment Implementation

Spinal muscular atrophy (SMA) encompasses a group of autosomal recessively inherited degenerative neuromuscular disorders. They range in severity from neonatal onset with rapidly progressive weakness and early mortality (SMA-1), to onset in infancy (SMA-2), to adolescent/adult onset with indolent clinical course (SMA-3/-4). SMA patients share mutations in the survival motor neuron (SMN) gene; variations in clinical phenotypes are attributable to copy numbers of the closely related SMN2 gene. In December 2016, the US Food and Drug Administration (FDA) approved nusinersen (Spinraza, Biogen, Cambridge, MA) to treat SMA. Nusinersen, an antisense oligonucleotide, is administered directly into cerebrospinal fluid. It alters SMN2 pre-RNA splicing so exon 7 is included, increasing expression of functional SMN protein. Although nusinersen was FDA approved for treatment of all forms of SMA, the initial clinical trials were limited to patients up to age 14 years, diagnosed with SMA-1,-2, -3, not on mechanical ventilation support. Two subsequent phase 3 trials were completed for SMA-1 and SMA-2/-3 and demonstrated improved motor milestones and event-free survival, better than expected based on natural history studies. Efficacy assessments for patients receiving nusinersen are based on serial assessments of performance on age-appropriate standardized motor scales. Treatment requires complex financial and logistics because of the very high drug cost, intrathecal administration, and medical fragility of the patients. Treatment implementation also engenders ethical considerations related to cost, insurance coverage, limited clinical data on groups of patients not in clinical trials, and questions of duration of treatment. Nusinersen has been integrated into the treatment of many SMA patients.

Quantitative Motion Measurements Based on Markerless 3D Full-Body Tracking in Children with SMA Highly Correlate with Standardized Motor Assessments

2021 ◽  
pp. 1-8
Author(s):  
Astrid Blaschek ◽  
Nikolas Hesse ◽  
Birgit Warken ◽  
Katharina Vill ◽  
Therese Well ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Body Motion ◽  
Therapeutic Interventions ◽  
Whole Body ◽  
Absolute Distance ◽  
Depth Sensor ◽  
Motion Parameters ◽  
Full Body

Background: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. Objective: Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. Methods: We have developed a system for tracking full-body motion in infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2–46 months of age; CHOP INTEND score 10–50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. Results: 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3–1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6–10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8–8.5%). Conclusions: Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages.

scholarly journals A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nozomu Matsuda ◽  
Koushi Ootsuki ◽  
Shunsuke Kobayashi ◽  
Ayaka Nemoto ◽  
Hitoshi Kubo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Neuromuscular Disorders ◽  
Whole Body ◽  
Congenital Hearing Loss ◽  
Severe Phenotype ◽  
Demyelinating Neuropathy ◽  
Magnetic Resonance Neurography ◽  
Peripheral Myelin Protein 22 ◽  
Hypertrophic Neuropathy

Abstract Background Hereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2. Case presentation The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2. Conclusions We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

scholarly journals Becker muscular dystrophy associated with sarcomeric hypertrophic cardiomyopathy in a paediatric patient: a case report

2019 ◽  
Vol 3 (3) ◽  
Author(s):  
Paola Dolader ◽  
Ella Field ◽  
Anna Sarkozy ◽  
Juan Pablo Kaski
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Muscular Dystrophy ◽  
Neuromuscular Disorders ◽  
Elevated Serum ◽  
Becker Muscular Dystrophy ◽  
Neuromuscular Disorder ◽  
Chain Gene ◽  
Septal Hypertrophy ◽  
History Of ◽  
Myocardial Involvement

Abstract Background  Becker muscular dystrophy (BMD) is a neuromuscular disorder associated with myocardial involvement. The most frequent presentation is dilated cardiomyopathy. There have been isolated reports of hypertrophic cardiomyopathy (HCM) in association with BMD, but it is unclear whether these patients had an additional aetiology. Case summary  A 10-year-old boy was diagnosed with BMD having presented with a history of muscular pain during exercise and elevated serum creatine kinase levels. A cardiac screening was arranged and the echocardiogram confirmed an asymmetric septal hypertrophy. Given the unusual finding of HCM in this patient with BMD, we performed genetic testing for HCM-causing mutations and identified a likely pathogenic variant in heterozygosis in the beta-myosin heavy chain gene. Discussion  This case highlights the importance of considering additional aetiologies of cardiac disease in the presence of infrequent phenotypic expressions in neuromuscular disorders.

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