The sense of antisense therapies in ALS

Van Daele, Sien H.; Masrori, Pegah; Van Damme, Philip; Van Den Bosch, Ludo

doi:10.1016/j.molmed.2023.12.003

Cited by 18 publications

(7 citation statements)

References 72 publications

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“…There has recently been renewed efforts in the development of therapeutics for ALS [ 216 ] invoking the potential role of mitochondria [ 217 ] and the gut–brain axis [ 218 ], as well as anti-sense therapies [ 219 ] and personalized immunotherapy [ 220 ]. Future efforts to better understand the pathogenesis of ALS and screen for effective treatments will use human organoids composed of iPSC [ 221 , 222 ] discussed in the last section.…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

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Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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“…Another ASO therapy concerns Stathmin-2 ( STMN2 ) (NCT05633459), which acts as an important splice target of TDP-43 (TAR DNA-binding protein 43), and thus the loss of nuclear TDP-43, as observed in ALS leading to a Stathmin-2 mis-splicing. While the clinical trial of this ASO therapy is ongoing, the Stathmin-2 levels have been restored in preclinical studies and could transform the therapeutical options for ALS patients [ 62 , 63 ]. The failure of the C9orf72 trials (NCT03626012, NCT04931862) revealed the indispensability of understanding the precise pathophysiological mechanism of distinct subgroups, although the exact reason for this failure is still unknown [ 62 ].…”

Section: Genetic and Related Pathophysiological Heterogeneitymentioning

confidence: 99%

“…While the clinical trial of this ASO therapy is ongoing, the Stathmin-2 levels have been restored in preclinical studies and could transform the therapeutical options for ALS patients [ 62 , 63 ]. The failure of the C9orf72 trials (NCT03626012, NCT04931862) revealed the indispensability of understanding the precise pathophysiological mechanism of distinct subgroups, although the exact reason for this failure is still unknown [ 62 ]. Hence, new therapeutic approaches targeting particular mechanisms involved in specific mutations are important in addition to ASO treatments.…”

Section: Genetic and Related Pathophysiological Heterogeneitymentioning

confidence: 99%

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Tzeplaeff,

Jürs,

Wohnrade

et al. 2024

Cells

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Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.

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“…Recently, on April 2023, the first antisense oligonucleotide (ASO) called tofersen (also known as BIIB067 with the trade name Qalsody) has been approved for patients suffering from both forms of sporadic ALS (sALS) and familial ALS (fALS) targeting mutations in superoxide dismutase 1 (SOD1) messenger ribonucleic acid (mRNA). [7,8] Toferson (ASOs), designed to degrade the mRNA as a result, downregulate the toxicity aggregation of SOD1 protein levels. [7] Another, synthetic ASO MAPTRx (ISIS 814907/BIIB080) is designed to deduce the toxic concentrations of microtubuleassociated protein tau (MAPT) messenger RNA in AD patients.…”

Section: Introductionmentioning

confidence: 99%

“…[7,8] Toferson (ASOs), designed to degrade the mRNA as a result, downregulate the toxicity aggregation of SOD1 protein levels. [7] Another, synthetic ASO MAPTRx (ISIS 814907/BIIB080) is designed to deduce the toxic concentrations of microtubuleassociated protein tau (MAPT) messenger RNA in AD patients. The current phase 1b, randomized, placebo-controlled trial evaluated the dose-dependent reductions in total cerebrospinal fluid (CSF) tau concentrations in the brain of AD patients.…”

Section: Introductionmentioning

confidence: 99%

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Sanghai,

Vuong,

Burak Berk

et al. 2024

ChemMedChem

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Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule‐based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule‐based novel approaches to target NDDs, such as designing lipophilic molecules, applying prodrug strategies and utilizing a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web‐based computational tools. Further, to increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs and to increase our awareness of neurodegenerative therapeutics.

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The sense of antisense therapies in ALS

Cited by 18 publications

References 72 publications

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

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