Antisense oligonucleotides (ASOs) are promising for targeting diseases by modulating gene expression, even for genes previously considered "undruggable." ASOs enter cells through endocytosis but face challenges as they often get trapped in endosomes, limiting their therapeutic effect. Strategies to enhance endosomal escape, including using endosomal escape agents and non-viral delivery vehicles, are critical to increase their effectiveness. Despite some success, only 1-2% of ASOs reach the target mRNA in the …

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This paper investigates a potential treatment for facioscapulohumeral muscular dystrophy (FSHD), a genetic disorder caused by the improper expression of the DUX4 gene in muscles, leading to muscle weakness and deterioration. Currently, there is no molecular therapy to halt or slow the progression of FSHD. The researchers tested an antisense oligonucleotide (ASO) that targets and reduces the DUX4 transcript in a mouse model (ACTA1-MCM;FLExDUX4) that mimics FSHD. The ASO treatment, …

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Casimersen (AMONDYS 45™) is a therapeutic antisense oligonucleotide designed for patients with Duchenne Muscular Dystrophy (DMD) whose gene mutation is amenable to exon 45 skipping. DMD is a genetic disorder characterized by the absence of dystrophin, a crucial protein for muscle function. This results in progressive muscle degeneration and loss of mobility, eventually affecting the heart and lungs. Casimersen works by binding to the mutated pre-mRNA, skipping exon 45 to …

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1. Propensity Score Matching      A statistical method used to balance groups in observational studies, reducing bias by matching individuals with similar characteristics. This helps improve the validity of comparisons, especially in studies where randomization isn't possible. 2. North Star Ambulatory Assessment (NSAA) and North Star Assessment    These are clinical tools used to measure motor abilities in patients with neuromuscular disorders. The NSAA, for example, is frequently used …

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This paper introduces a novel therapeutic approach for Duchenne Muscular Dystrophy (DMD) using NS-089/NCNP-02, an antisense oligonucleotide (ASO) designed to skip exon 44 of the dystrophin gene. DMD is a severe muscle disorder caused by mutations in the DMD gene, leading to a lack of dystrophin protein. Exon skipping helps to restore the reading frame of dystrophin, enabling the production of a shorter but functional dystrophin protein. The authors focused …

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The paper titled "Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects and Challenges" explores an advanced therapeutic strategy for treating Duchenne Muscular Dystrophy (DMD), a severe genetic disorder caused by mutations in the dystrophin gene. This mutation leads to the absence of functional dystrophin protein, which is essential for maintaining muscle integrity. One emerging treatment method involves antisense oligonucleotide (AO)-mediated exon skipping, where specific exons are skipped …

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Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder affecting males, characterized by muscle degeneration and early death. Antisense-mediated exon skipping therapy offers a new hope by producing a truncated but functional dystrophin protein. Casimersen (Amondys 45) specifically targets exon 45 of the dystrophin gene, which applies to about 8% of DMD patients. The drug was approved by the FDA in 2021, based on its promising preclinical and phase I/II …

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The paper presents findings from a phase 3 clinical trial (EMBARK) evaluating the efficacy and safety of a gene therapy, delandistrogene moxeparvovec, in patients with Duchenne muscular dystrophy (DMD). DMD is a severe, inherited condition that progressively weakens muscles due to the absence of dystrophin. The therapy uses an AAV vector to deliver a functional dystrophin gene into muscle cells. The trial involved boys aged 4 to 8, who were …

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Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by motor neuron degeneration, often leading to death within a few years. While there are limited treatments, genetic mutations in superoxide dismutase 1 (SOD1) have been identified in 2% of ALS cases. Tofersen, an antisense oligonucleotide (ASO), specifically targets SOD1 mRNA, reducing the production of toxic SOD1 protein and has shown promise in clinical trials, resulting in FDA approval in …

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The abbreviations listed below are directly related to the most recent article I shared, which focuses on neuromuscular disorders and the molecular pathways involved. These terms help explain the key findings and methodologies discussed in the study.   DEP (Differential Expressed Protein):   This refers to proteins that show significant differences in their levels between two conditions, such as healthy versus diseased tissue. Studying these proteins helps scientists understand the …

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