Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen

Genes, Год журнала: 2024, Номер 15(10), С. 1342 - 1342

Опубликована: Окт. 20, 2024

Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years onset. There have been few effective treatments, making development robust therapies an urgent challenge. Genetic mutations identified as contributors to ALS, with

Язык: Английский

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Drug Combination to Slow Down the Progression of Amyotrophic Lateral Sclerosis

Current Treatment Options in Neurology, Год журнала: 2025, Номер 27(1)

Опубликована: Апрель 2, 2025

Язык: Английский

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Tauroursodeoxycholic Acid Protects Retinal Ganglion Cells and Reduces Inflammation in Mice Following Optic Nerve Crush

Pharmaceuticals, Год журнала: 2025, Номер 18(4), С. 569 - 569

Опубликована: Апрель 14, 2025

Purpose: The aim of this study was to investigate the protective effects systemically administered tauroursodeoxycholic acid (TUDCA) in an optic nerve crush (ONC) mouse model retinal ganglion cell (RGC) death. Methods: C57BL/6J mice were injected intraperitoneally (i.p.) three times per week with TUDCA (500 mg/kg) for two weeks, after which unilateral ONC performed. A control cohort identically treated a drug vehicle (phosphate buffered saline; PBS). separate did not undergo any injections or surgeries (this termed “Naïve” group). Pattern electroretinography (PERG) recorded 3 days ONC. Retinas harvested whole-mount immunofluorescence staining antibody against RGC marker Brn3a and imaged by fluorescent confocal microscopy. Apoptotic cells layer (GCL) detected Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (TUNEL) performed on fixed retina sections. Glial fibrillary acidic protein (GFAP) immunostaining sections conducted detect activation Müller cells. Total RNA extracted from retinas expression interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-10 determined digital droplet PCR (ddPCR). Results: treatment preserved visual function as assessed PERG. P1 N2 amplitudes PBS-treated group significantly diminished compared those Naïve (p < 0.001). prevented diminution. TUDCA-treated statistically indistinguishable higher than (TUDCA+ONC vs. PBS+ONC, P1: 6.99 ± 0.89 µV 3.60 0.69 µV, p 0.01; N2: −9.30 (IQR: −13.43–−6.44) −4.47 −10.26–−2.17) µV). RGCs. ONC-vehicle-only had 25% fewer RGCs (Brn3a-positive cells) eyes 0.0001). nearly completely loss, preserving all but 7.7% RGCs, number 1738.00 14.43 field 1454.00 6.55 field, TUNEL-positive GCL (Naïve PBS+ONC group: 1.00 0.00–2.00) % 37.00 8.50–48.50) %, 0.05) GFAP-positive fibers transversing 33.00 1.15 185.70 42.37 fibers/retina, 0.05), TNF-α greater that group, IL-6: 0.07 0.06–0.31) 0.99 0.56–1.47), 0.05, TNF-α: 0.19 0.069 1.39 0.23; 0.01), increase observed treatment. Conclusions: Systemic survival damage. apoptosis, glial activation, several inflammatory cytokines. These data suggest is promising therapeutic candidate numbers function.

Язык: Английский

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Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies

Life, Год журнала: 2025, Номер 15(4), С. 647 - 647

Опубликована: Апрель 14, 2025

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, respiratory failure. This comprehensive review synthesizes current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, evolving therapeutic strategies. Mechanistically, arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), FUS) dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, prion-like propagation toxic aggregates. Phenotypic manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates rigorous application revised El Escorial criteria emerging biomarkers such neurofilament light chain. Clinically, intersects with frontotemporal dementia (FTD) up 50% cases, driven shared TDP-43 pathology C9orf72 hexanucleotide expansions. Epidemiological studies have revealed lifetime risk 1:350, male predominance (1.5:1) peak onset 50 70 years. Disease progression varies widely, median survival 2–4 years post-diagnosis, underscoring urgency for intervention. Approved therapies, riluzole (glutamate modulation), edaravone (antioxidant), tofersen (antisense oligonucleotide), offer modest benefits, while dextromethorphan/quinidine alleviates pseudobulbar affect. Non-pharmacological treatment advances, non-invasive ventilation (NIV), prolong 13 months improve quality life, particularly bulb-involved patients. Multidisciplinary care—integrating physical therapy, support, nutritional management, cognitive assessments—is critical addressing non-motor symptoms dysphagia, spasticity, sleep disturbances). Emerging therapies show promise preclinical models. However, challenges persist translating insights into universally effective treatments. Ethical considerations, euthanasia end-of-life decision-making, further highlight need patient-centered communication palliative

Язык: Английский

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Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis

Current Opinion in Neurology, Год журнала: 2024, Номер 37(5), С. 593 - 602

Опубликована: Июль 31, 2024

Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number promising test drugs pipeline along with existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval Japan. Clinical trial design best suited for ALS also be discussed.

Язык: Английский

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A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Год журнала: 2024, Номер unknown, С. 1 - 10

Опубликована: Сен. 10, 2024

: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure amyotrophic lateral sclerosis (ALS). clinical and economic uncertainty surrounding innovative treatments rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). aim of this study was review whether models MEAs in SMA could be extrapolated ALS.

Язык: Английский

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The Scientific and Therapeutic Rationale for Off‐Label Treatments in Amyotrophic Lateral Sclerosis

Annals of Neurology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 6, 2024

There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by group called ALSUntangled to identify 8 alternative off‐label that target ≥1 these have human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms highlighted products, we suggest combinations targeting diverse might be worthwhile future sclerosis therapy development. ANN NEUROL 2024

Язык: Английский

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Emerging concepts and therapies for amyotrophic lateral sclerosis

Current Opinion in Neurology, Год журнала: 2024, Номер 37(5), С. 558 - 559

Опубликована: Сен. 3, 2024

Язык: Английский

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