Articles: oligonucleotides.
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Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. ⋯ Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.
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Randomized Controlled Trial Multicenter Study
Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. ⋯ In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
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NrCAM, a neuronal cell adhesion molecule in the L1 family of the immunoglobulin superfamily, is subjected to extensively alternative splicing and involved in neural development and some disorders. The aim of this study was to explore the role of Nrcam mRNA alternative splicing in neuropathic pain. A next generation RNA sequencing analysis of dorsal root ganglions (DRGs) showed the differential expression of two splicing variants of Nrcam, Nrcam+10 and Nrcam-10, in the injured DRG after the fourth lumbar spinal nerve ligation (SNL) in mice. ⋯ Nrcam ASO also relieved SNL- or chronic compression of DRG (CCD)-induced the maintenance of pain hypersensitivities in male and female mice. PERSPECTIVE: We conclude that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis. Targeting Nrcam alternative splicing via the antisense oligonucleotides may be a new potential avenue in neuropathic pain management.
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Eur. J. Paediatr. Neurol. · Jul 2020
Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: Real world data from Hungarian patients.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a homozygous deletion of the survival motor neuron (SMN) 1 gene. Nusinersen is an antisense oligonucleotide enhancing the production of the SMN protein. It has received approval by the European Medicines Agency (EMA) in 2017, based on the clinical trials demonstrating the effectiveness of nusinersen in several types of SMA. In Hungary, the first patient received nusinersen treatment in April 2018. Our aim is to summarize our experience regarding the efficacy, safety and tolerability of nusinersen in our patients. ⋯ According to our results nusinersen has the same safety and tolerability profile as in the clinical trials. In a heterogenic patient population of SMA type 1 and 2, nusinersen showed similar efficacy as seen in the pivotal studies. A clinically and statistically significant improvement of motor functions was also detectable in type 3 patients with heterogeneous age distribution.
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The present global health emergency involving the emergence and rapid spread of a novel coronavirus has prompted the world scientific community to consider how it can help to fight this growing viral pandemic. With few safe and effective drugs available to combat this threat to humanity and the normal functioning of our society, the oligonucleotide research community is uniquely positioned to apply its technology and expertise to help alleviate the crisis, thanks to its capacity for rational drug design, swift development cycles, and pursuing targets undruggable by conventional treatment strategies.