The sense of antisense therapies in ALS

Trends in Molecular Medicine, Год журнала: 2024, Номер 30(3), С. 252 - 262

Опубликована: Янв. 11, 2024

Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and first ASO therapy for ALS been approved by the FDA. Moreover, there is hope not only can be stopped but also symptoms reversed. Until now, degrading ASOs seemed to successful mostly rarer forms familial ALS. However, attempts correct mis-splicing events in sporadic underway, as well clinical trial examining interference genetic modifier. In this review, we discuss current status using possibilities pitfalls therapeutic strategy.

Язык: Английский

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Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics

The Lancet Neurology, Год журнала: 2025, Номер 24(3), С. 261 - 274

Опубликована: Фев. 19, 2025

Язык: Английский

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Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Март 2, 2024

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, spinal cord. Unfortunately, there are few effective treatments, thus remains critical need to find novel interventions that can mitigate against its effects. Whilst aetiology of ALS unclear, ageing major risk factor. Ageing slowly progressive process marked by functional decline an organism over lifespan. However, it unclear how promotes ALS. At molecular cellular level specific hallmarks characteristic normal ageing. These highly inter-related overlap significantly with each other. Moreover, whilst process, striking similarities at between these factors neurodegeneration Nine were originally proposed: genomic instability, loss telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, proteostasis, mitochondrial dysfunction, stem cell exhaustion, altered inter-cellular communication. recently (2023) expanded include dysregulation autophagy, inflammation dysbiosis. Hence, given latest updates hallmarks, their close association disease processes ALS, new examination relationship pathophysiology warranted. In this review, we describe possible mechanisms which impacts on neurodegenerative implicated therapeutic may arise from this.

Язык: Английский

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Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study

European Journal of Neurology, Год журнала: 2024, Номер 31(9)

Опубликована: Июнь 10, 2024

To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes amyotrophic lateral sclerosis (ALS).

Язык: Английский

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Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4809 - 4809

Опубликована: Апрель 28, 2024

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels functional proteins, and decrease toxic proteins. being developed for the treatment motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) bulbar (SBMA). The biggest success has been ASO known as nusinersen, first effective therapy SMA, able improve symptoms slow disease progression. Another is tofersen, an treat ALS patients with SOD1 gene mutations. Both have approved by FDA EMA. On other hand, in C9orf72 mutation did not show any improvement aim this review provide up-to-date overview research MNDs, from preclinical studies clinical trials and, where available, regulatory approval. We highlight successes failures, underline strengths limitations current research, suggest possible approaches that could lead more treatments.

Язык: Английский

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Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis

Nature Reviews Neurology, Год журнала: 2025, Номер 21(2), С. 86 - 102

Опубликована: Янв. 2, 2025

Язык: Английский

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C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

Deleted Journal, Год журнала: 2024, Номер 1(4)

Опубликована: Окт. 1, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb as highly compacted chromatin embedded an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources DNA. Cells from contained a rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate deficiency. Age-dependent can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome fragility, adding structural variations disease-enriched 9p21 likely elsewhere.

Язык: Английский

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Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 9966 - 9966

Опубликована: Сен. 15, 2024

This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well emerging treatments. The purpose is to condense key findings illustrate the complexity ALS, which shaped by both genetic environmental influences. We reviewed literature discuss recent advancements in understanding molecular mechanisms such protein misfolding, mitochondrial dysfunction, oxidative stress, axonal transport defects, are critical for identifying potential therapeutic targets. Significant progress has been made refining criteria biomarkers, leading earlier more precise diagnoses. Although drug treatments provide some benefits, there a clear need effective therapies. Emerging treatments, gene therapy stem cell therapy, show modifying disease progression improving quality life ALS patients. emphasizes importance continued research address challenges variability limited effectiveness existing Future should concentrate on further exploring foundations developing new approaches. implications practice include ensuring accessibility that healthcare systems equipped support ongoing patient care.

Язык: Английский

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Brain distribution study of [14C]-Riluzole following intranasal administration in mice

International Journal of Pharmaceutics, Год журнала: 2025, Номер 670, С. 125195 - 125195

Опубликована: Янв. 8, 2025

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery enhance CNS riluzole (RLZ), standard ALS which is subject blood-brain barrier efflux mechanisms. Additionally, impact elacridar (ELC), an pump inhibitor, on IN RLZ bioavailability was examined. To quantify vivo mice, [14C]-RLZ synthesised using optimised one-pot method. yield 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with specific activity 40.4 3.9 µCi/mg HPLC liquid scintillation counting. synthesis verified proton nuclear magnetic resonance (1H NMR), chromatography-mass spectrometry. (5 mg/kg) produced double maximum brain levels (1.11 0.34 % Injected Dose (ID)/brain) at 30 min as oral mg/kg). The uptake liver reduced half for administration compared administration. Intravenous ELC substantially increased 3.52 0.62 ID/g 60 post-administration, 1.87 0.33 absence inhibitor. However, concentrations were also observed blood. These results indicate that enhances targeting reduces accumulation route. Brain enhanced further ELC, although not selectively or blood observed. Further metabolic research Chromatography-Mass spectrometry (LC-MS) NMR along excretion studies are warranted more comprehensive understanding pharmacokinetics RLZ/ELC. employing suitable animal models crucial RLZ's effects progression, mechanism action, efficacy, side aid development.

Язык: Английский

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Report on the 6th Ottawa International Conference on Neuromuscular Disease & Biology – September 7–9, 2023, Ottawa, Canada

Journal of Neuromuscular Diseases, Год журнала: 2025, Номер 12(1)

Опубликована: Янв. 1, 2025

The 6th Ottawa International Conference in Neuromuscular Disease and Biology was held on September 7–9, 2023 Ottawa, Canada. goal of the conference to assemble international experts fundamental science, translational medicine clinical neuromuscular disease research. Speakers provided attendees with updates a wide range topics related biology, including methods identify novel diseases, recent developments muscle, motor neuron stem cell expanded pathogenesis known exciting advances therapy development. A summary major results presented by these speakers is provided.

Язык: Английский

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