scholarly journals Antisense Oligonucleotide Therapy for Neurodevelopmental Disorders

2021 ◽  
pp. 1-6
Author(s):  
Sophie F. Hill ◽  
Miriam H. Meisler
Keyword(s):  
Neurodevelopmental Disorders ◽  
Antisense Oligonucleotides ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Genetic Disorders ◽  
Neuromuscular Disorders ◽  
Epileptic Encephalopathy ◽  
Mrna Splicing ◽  
Patient Specific ◽  
Antisense Oligonucleotide Therapy

Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. The FDA has approved ASOs for treatment of ten genetic disorders, with many applications currently in the pipeline. We describe the molecular mechanisms of ASO treatment for four neurodevelopmental and neuromuscular disorders. The ASO nusinersen is a general treatment for mutations of <i>SMN1</i> in spinal muscular atrophy that corrects the splicing defect in the <i>SMN2</i> gene. Milasen is a patient-specific ASO that rescues splicing of <i>CNL7</i> in Batten’s disease. STK-001 is an ASO that increases expression of the sodium channel gene <i>SCN1A</i> by exclusion of a poison exon. An ASO that reduces the abundance of the <i>SCN8A</i> mRNA is therapeutic in mouse models of developmental and epileptic encephalopathy. These examples demonstrate the variety of mechanisms and range of applications of ASOs for treatment of neurodevelopmental disorders.

scholarly journals Wrangling RNA: Antisense oligonucleotides for neurological disorders

2019 ◽  
Vol 11 (511) ◽  
pp. eaay2069 ◽  
Author(s):  
Kevin Talbot ◽  
Matthew J. A. Wood
Keyword(s):  
Spinal Muscular Atrophy ◽  
Effective Treatment ◽  
Neurological Disorders ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Antisense Oligonucleotide Therapy

Effective treatment of spinal muscular atrophy with antisense oligonucleotide therapy opens the door to treating other neurological disorders with this approach.

scholarly journals Antisense Oligonucleotide Gene Therapy for Neuromuscular Disorders

2018 ◽  
Vol 8 (2) ◽  
pp. 11-14
Author(s):  
Ryan Gotesman
Keyword(s):  
Gene Therapy ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Transthyretin Amyloidosis ◽  
Gene Therapies ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Lateral Sclerosis ◽  
Specific Mrna

Antisense oligonucleotides (ASOs) are synthetic, single-stranded DNA molecules that can bind to specific mRNA sequences and alter protein expression. ASO gene therapies are leading to breakthroughs in the treatment of once intractable neuromuscular disorders. In 2016, ASOs became the first FDA-approved drugs for treating spinal muscular atrophy and Duchenne muscular dystrophy. Recent trials also suggest ASOs may be effective in combating Huntington’s disease, amyotrophic lateral sclerosis and hereditary transthyretin amyloidosis. This article highlights ASOs’ mechanism of action, their use in treating neuromuscular disease and future obstacles the gene therapy must overcome, providing an update on the state of ASO technology.

Exercise biology of neuromuscular disorders

2018 ◽  
Vol 43 (11) ◽  
pp. 1194-1206 ◽  
Author(s):  
Sean Y. Ng ◽  
Alexander Manta ◽  
Vladimir Ljubicic
Keyword(s):  
Molecular Mechanisms ◽  
Acute Exercise ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular System ◽  
Cellular Mechanisms ◽  
Disease Mechanisms ◽  
Exercise Adaptation ◽  
Exercise Induced

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.

scholarly journals A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study

2020 ◽  
Vol 10 (4) ◽  
pp. 281
Author(s):  
Syuan-Yu Hong ◽  
Jiann-Jou Yang ◽  
Shuan-Yow Li ◽  
Inn-Chi Lee
Keyword(s):  
Pediatric Patients ◽  
Novel Mutation ◽  
Wide Spectrum ◽  
Genetic Disorders ◽  
Neuromuscular Disorders ◽  
Case Series ◽  
Epileptic Encephalopathy ◽  
High Yield ◽  
Whole Exome ◽  
Refractory Seizures

Background: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients. Methods: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES. Results: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345–7,739,782)X1, 17q25.1q25.3(73,608,322–81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series. Conclusions: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients.

Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 239-252
Keyword(s):  
Molecular Mechanisms ◽  
Protein Localization ◽  
Regulation Of Gene Expression ◽  
Neuronal Cell ◽  
Mrna Splicing ◽  
Genetic Mutations ◽  
Scaffolding Proteins ◽  
Molecular Processes ◽  
Genetic Studies ◽  
Novel Treatments

In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

scholarly journals Silencing Antibiotic Resistance with Antisense Oligonucleotides

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 416
Author(s):  
Saumya Jani ◽  
Maria Soledad Ramirez ◽  
Marcelo E. Tolmasky
Keyword(s):  
Antibiotic Resistance ◽  
Nucleic Acids ◽  
Antisense Oligonucleotides ◽  
Bacterial Infections ◽  
Genetic Disorders ◽  
Antibiotic Resistance Genes ◽  
Short Review ◽  
Rnase H ◽  
Biological Processes ◽  
Locked Nucleic Acids

Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics.

scholarly journals Could metabolomics drive the fate of COVID-19 pandemic? A narrative review on lights and shadows

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michele Mussap ◽  
Vassilios Fanos
Keyword(s):  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Asymptomatic Infection ◽  
Multiple Organ ◽  
Therapeutic Interventions ◽  
Patient Specific ◽  
Wide Range ◽  
Life Threatening ◽  
The Individual ◽  
Host Metabolism

Abstract Human Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection activates a complex interaction host/virus, leading to the reprogramming of the host metabolism aimed at the energy supply for viral replication. Alterations of the host metabolic homeostasis strongly influence the immune response to SARS-CoV-2, forming the basis of a wide range of outcomes, from the asymptomatic infection to the onset of COVID-19 and up to life-threatening acute respiratory distress syndrome, vascular dysfunction, multiple organ failure, and death. Deciphering the molecular mechanisms associated with the individual susceptibility to SARS-CoV-2 infection calls for a system biology approach; this strategy can address multiple goals, including which patients will respond effectively to the therapeutic treatment. The power of metabolomics lies in the ability to recognize endogenous and exogenous metabolites within a biological sample, measuring their concentration, and identifying perturbations of biochemical pathways associated with qualitative and quantitative metabolic changes. Over the last year, a limited number of metabolomics- and lipidomics-based clinical studies in COVID-19 patients have been published and are discussed in this review. Remarkable alterations in the lipid and amino acid metabolism depict the molecular phenotype of subjects infected by SARS-CoV-2; notably, structural and functional data on the lipids-virus interaction may open new perspectives on targeted therapeutic interventions. Several limitations affect most metabolomics-based studies, slowing the routine application of metabolomics. However, moving metabolomics from bench to bedside cannot imply the mere determination of a given metabolite panel; rather, slotting metabolomics into clinical practice requires the conversion of metabolic patient-specific data into actionable clinical applications.

scholarly journals Advances in hepatic transport: Molecular mechanisms, genetic disorders, and treatment. A summary of the 1998 AASLD single topic conference

Hepatology ◽  
1998 ◽  
Vol 28 (6) ◽  
pp. 1713-1719 ◽  
Author(s):  
Allan W. Wolkoff ◽  
Frederick J. Suchy ◽  
Richard H. Moseley ◽  
Peter J. Meier ◽  
John L. Gollan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Disorders ◽  
Hepatic Transport
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