scholarly journals Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Mengsi Lin ◽  
Xinyi Hu ◽  
Shiyi Chang ◽  
Yan Chang ◽  
Wenjun Bian ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Neurodegenerative Diseases ◽  
Target Genes ◽  
Muscular Atrophy ◽  
Clinical Stage ◽  
Neuromuscular Diseases ◽  
Protein Translation ◽  
The Us ◽  
Posttranscriptional Processing ◽  
Us Fda

Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.

Regulatory decisions from the US FDA

2001 ◽  
Vol &NA; (1272) ◽  
pp. 22
Author(s):  
&NA;
Keyword(s):  
The Us ◽  
Us Fda ◽  
Regulatory Decisions

scholarly journals Industry update for May 2019

2019 ◽  
Vol 10 (9) ◽  
pp. 555-561
Author(s):  
Louise Rosenmayr-Templeton
Keyword(s):  
Gene Therapy ◽  
Cost Effectiveness ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Clinical Results ◽  
The Other ◽  
Press Releases ◽  
The Us ◽  
True Meaning ◽  
Genetic Medicine

This industry update features a round-up of pharmaceutical news in May 2019 based on press releases and websites. The month was characterized by the achievement of significant milestones in gene therapy. The biggest of these was the US FDA’s approval of Zolgensma®. This medicine sums up the promise and price of genetic medicine. On one hand the clinical results show Zolgensma can dramatically improve the prognosis for infants with spinal muscular atrophy after just one administration, while on the other, it has been priced at around US$2.1 million. With more such therapies likely to reach the market, the debate on Zolgensma goes beyond cost, to overall affordability, the true meaning of cost–effectiveness and how to reward companies for effective, innovative medicines.

scholarly journals Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Dunhui Li ◽  
Craig Stewart McIntosh ◽  
Frank Louis Mastaglia ◽  
Steve Donald Wilton ◽  
May Thandar Aung-Htut
Keyword(s):  
Alternative Splicing ◽  
Neurodegenerative Diseases ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Single Gene ◽  
Synaptic Function ◽  
Coding Regions ◽  
Splicing Defects ◽  
The Impact ◽  
Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

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

scholarly journals Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 75 ◽  
Author(s):  
Nicoletta Nuzziello ◽  
Loredana Ciaccia ◽  
Maria Liguori
Keyword(s):  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Target Genes ◽  
Drug Disposition ◽  
Therapeutic Potential ◽  
Response To Treatment ◽  
Therapeutic Effects ◽  
Exciting Potential ◽  
The Central Nervous System ◽  
Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

scholarly journals Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria

2019 ◽  
Vol 10 ◽  
pp. 204062071987472 ◽  
Author(s):  
Robert M. Stern ◽  
Nathan T. Connell
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Phase Iii ◽  
The European Union ◽  
Regulatory Review ◽  
Dosing Schedule ◽  
The Us ◽  
United States Food ◽  
States Food ◽  
Us Fda

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. Until recently, the complement inhibitor, eculizumab, was the only United States Food and Drug Administration (US FDA)-approved therapy for the treatment of PNH. Although effective, eculizumab requires a frequent dosing schedule that can be burdensome for some patients and increases the risk of breakthrough intravascular hemolysis. Ravulizumab, an eculizumab-like monoclonal antibody engineered to have a longer half-life, is intended to provide the same benefits as eculizumab but with a more convenient and effective dosing schedule. In two recently published phase III non-inferiority trials, ravulizumab was found to be non-inferior to eculizumab both in efficacy and safety for the treatment of patients with PNH. Based on these results, ravulizumab was approved by the US FDA on 21 December 2018 and is currently under regulatory review in both the European Union and Japan.

scholarly journals Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration

2019 ◽  
Vol 27 ◽  
pp. 204020661982938 ◽  
Author(s):  
Erik De Clercq
Keyword(s):  
Autologous Transplantation ◽  
Hepatopulmonary Syndrome ◽  
Blood Stream ◽  
Malignant Diseases ◽  
Whim Syndrome ◽  
Natural Ligand ◽  
Cxcr4 Receptor ◽  
The Us ◽  
Us Fda ◽  
Anti Hiv

AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34+stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin’s Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.

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