Articles: oligonucleotides.
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Activation of transient receptor potential ankyrin 1 (TRPA1) channels by both environmental irritants and endogenous inflammatory mediators leads to excitation of the nerve endings, resulting in acute sensation of pain, itch, or chronic neurogenic inflammation. As such, TRPA1 channels are actively pursued as therapeutic targets for various pathological nociception and pain disorders. We uncovered that exon 27 of human TRPA1 (hTRPA1) could be alternatively spliced into hTRPA1_27A and hTRPA1_27B splice variants. ⋯ Knockdown of SRSF1, mutation within exonic splicing enhancer, or masking SRSF1 binding with antisense oligonucleotides promoted alternative splicing within exon 27. Finally, antisense oligonucleotides-induced alternative splicing produced transcript and protein variants that could be functionally determined as diminished endogenous TRPA1 activity in human Schwann cell-line SNF96.2 and hiPSCs-derived sensory neurons. The outcome of the work could potentially offer a novel therapeutic strategy for treating pain by targeting alternative splicing of hTRPA1.
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Lancet Child Adolesc Health · Jul 2021
Multicenter StudyTreatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years. ⋯ Biogen and Ionis Pharmaceuticals.
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Neuropathic pain remains an undertreated condition and there is a medical need to develop effective treatments. Accumulating evidence indicates that posttranscriptional regulation of gene expression is involved in neuropathic pain; however, RNA processing is not clearly investigated. Our study investigated the role of HuR, an RNA binding protein, in promoting neuropathic pain and trauma-induced microglia activation in the spared nerve injury mouse model. ⋯ An anti-HuR ASO inhibited the activation of spinal microglia by reducing the levels of proinflammatory cytokines, inducible nitric oxide synthase, the activation of nuclear factor-κB (NF-κB), and suppressed the spared nerve injury-induced overphosphorylation of spinal p38, ERK1/2 and c-Jun-N-terminal kinase (JNK)-1. In addition, HuR silencing increased the expression of the anti-inflammatory cytokine IL-10, promoting the shift of microglial M1 to M2 phenotype. Targeting HuR by i.n. anti-HuR ASO might represent a noninvasive promising perspective for neuropathic pain management by its powerful inhibition of microglia-mediated spinal neuroinflammation and promotion of an anti-inflammatory and neuroprotectant response.
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Eur. J. Paediatr. Neurol. · Mar 2021
Pediatric SMA patients with complex spinal anatomy: Implementation and evaluation of a decision-tree algorithm for administration of nusinersen.
The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. ⋯ In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.
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Am. J. Respir. Crit. Care Med. · Feb 2021
Randomized Controlled TrialA Phase 2a, Double-Blind, Placebo-Controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma.
Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma. Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial. Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/μl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; n = 40) or placebo (n = 41). ⋯ Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419. Conclusions: AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on FeNO is possible for patients with well-controlled asthma.