1. Background and Purpose: Antisense oligonucleotide (AO)-mediated exon skipping is a promising strategy for treating genetic disorders like Duchenne Muscular Dystrophy (DMD). This method alters dystrophin pre-mRNA splicing to create a shorter but functional protein, potentially converting severe DMD into a milder Becker Muscular Dystrophy (BMD) phenotype. The paper highlights the significance of skipping exons 45–55, a common mutation area that could help nearly half of DMD patients.   2. …

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I took some notes from the article and am happy to share them with anyone interested! The Problem: Antisense oligonucleotides (ASOs), which are designed to target and regulate specific genes, face two critical barriers limiting their therapeutic effectiveness: "endosomal entrapment” and “inefficient nuclear localization”. Only a small percentage of ASOs escape from endosomes to the cytosol and nucleus, preventing them from effectively modulating gene expression. The Potential Solution: Improving the …

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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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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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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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Personal take on this article: Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder caused by mutations in the dystrophin gene, leading to progressive muscle deterioration. The lack of functional dystrophin causes muscle weakness, cardiac and respiratory issues, and ultimately leads to early death. Traditional treatments like corticosteroids only delay the disease progression and are associated with serious side effects. In recent years, gene and antisense therapies have emerged as …

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  Personal take on this article: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive genetic disorder that primarily affects muscles of the face, shoulder girdle, and upper arms, with the potential to cause severe muscle atrophy over time. The disease is characterized by the aberrant expression of the DUX4 gene due to compromised epigenetic repression of the D4Z4 array, leading to toxic effects in muscle tissue. FSHD can be categorized into …

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    Personal take on this article:   The article titled "Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges" is a detailed review of the current advancements in gene-targeting treatments for Spinal Muscular Atrophy (SMA), a severe genetic disorder that leads to the loss of motor neurons, causing muscle weakness, loss of mobility, and potentially death if untreated. Key points: 1. SMA Overview: SMA is caused …

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  Personal take on this article:   This article explores dysferlinopathies, a group of muscular dystrophies leading to muscle weakness due to mutations in the DYSF gene. The gene is responsible for producing dysferlin, a vital protein for muscle membrane repair. The review covers the clinical aspects, molecular mechanisms, and emerging therapies for dysferlinopathies. It emphasizes the varied symptoms and the challenge of understanding how specific mutations relate to the …

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