Unlocking the potential of CRISPR-Cas9 for cystic fibrosis: A detailed review

Gene, Journal Year: 2025, Volume and Issue: unknown, P. 149257 - 149257

Published: Jan. 1, 2025

Language: Английский

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Gene editing flows to the lungs

Science, Journal Year: 2024, Volume and Issue: 384(6701), P. 1175 - 1176

Published: June 13, 2024

Intravenous targeting of airway basal cells for cystic fibrosis gene therapy overcomes lung barriers.

Language: Английский

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Plasmid Gene Therapy for Monogenic Disorders: Challenges and Perspectives

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(1), P. 104 - 104

Published: Jan. 14, 2025

Monogenic disorders are a group of human diseases caused by mutations in single genes. While some disease-altering treatments offer relief and slow the progression certain conditions, majority monogenic still lack effective therapies. In recent years, gene therapy has appeared as promising approach for addressing genetic disorders. However, despite advancements manipulation tools delivery systems, several challenges remain unresolved, including inefficient delivery, sustained expression, immunogenicity, toxicity, capacity limitations, genomic integration risks, limited tissue specificity. This review provides an overview plasmid-based techniques methods currently employed diseases, highlighting they face exploring potential strategies to overcome these barriers.

Language: Английский

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Adenine Base Editing with engineered Virus-Like Particles rescues the CFTR mutation G542X in patient-derived intestinal organoids

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111979 - 111979

Published: Feb. 21, 2025

Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores use of adenine base editing edit non-CF-causing G542R, recover function. Using editor engineered virus-like particles (BE-eVLPs) in patient-derived intestinal organoids, we achieved ∼2% G542X-to-G542R efficiency restored CFTR-mediated chloride transport ∼6.4% wild-type levels, independent treatment, with no bystander edits. This proof-of-principle demonstrates potential rescue provides foundation for future - vivo applications.

Language: Английский

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Evolution of Organoid Genetics

European Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 104(2), P. 151481 - 151481

Published: March 1, 2025

Language: Английский

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Transforming cancer treatment: integrating patient-derived organoids and CRISPR screening for precision medicine

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 25, 2025

The persistently high mortality rates associated with cancer underscore the imperative need for innovative, efficacious, and safer therapeutic agents, as well a more nuanced understanding of tumor biology. Patient-derived organoids (PDOs) have emerged innovative preclinical models significant translational potential, capable accurately recapitulating structural, functional, heterogeneous characteristics primary tumors. When integrated cutting-edge genomic tools such CRISPR, PDOs provide powerful platform identifying driver genes novel targets. This comprehensive review delves into recent advancements in CRISPR-mediated functional screens leveraging across diverse types, highlighting their pivotal role high-throughput genomics microenvironment (TME) modeling. Furthermore, this highlights synergistic potential integrating CRISPR immunotherapy, focusing on uncovering immune evasion mechanisms improving efficacy immunotherapeutic approaches. Together, these technologies offer promise advancing precision oncology.

Language: Английский

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Cutting-Edge Advances in Cystic Fibrosis: From Gene Therapy to Personalized Medicine and Holistic Management

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 402 - 402

Published: March 30, 2025

Cystic fibrosis (CF), a genetic disorder characterized by mutations in the CFTR gene, has seen significant advances treatment through cutting-edge approaches such as gene therapy and personalized medicine. This review examines current emerging strategies shaping CF care, focusing on novel therapies that target root cause of optimize patient outcomes. modulators have transformed cystic management enhancing protein function for specific mutations, leading to improved lung quality life. Concurrently, offers transformative potential aiming correct using tools like CRISPR/Cas9 or prime editing, though challenges remain delivery long-term efficacy. The integration precision medicine, facilitated genomic computational technologies, allows plans account variability disease severity. Complementing these approaches, holistic emphasizes importance psychological support nutritional optimization, acknowledging CF’s multi-system impact. Future directions include exploring anti-inflammatory agents microbiome modulation further mitigate morbidity. However, global disparities access continue challenge equitable healthcare delivery, underscoring need policy reform international cooperation. By synthesizing developments, this highlights modern treatments, advocating continued innovation equity, with ultimate goal dramatically improving life expectancy individuals CF.

Language: Английский

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Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: April 7, 2025

Language: Английский

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Trojan Horse-Like Vehicles for CRISPR-Cas Delivery: Engineering Extracellular Vesicles and Virus-Like Particles for Precision Gene Editing in Cystic Fibrosis

Human Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

The advent of genome editing has kindled the hope to cure previously uncurable, life-threatening genetic diseases. However, whether this promise can be ultimately fulfilled depends on how efficiently gene agents delivered therapeutically relevant cells. Over time, viruses have evolved into sophisticated, versatile, and biocompatible nanomachines that engineered shuttle payloads specific cell types. Despite advances in safety selectivity, long-term expression sustained by viral vectors remains a cause for concern. Cell-derived vesicles (CDVs) are gaining traction as elegant alternatives. CDVs encompass extracellular (EVs), diverse set intrinsically low-immunogenic membranous nanoparticles, virus-like particles (VLPs), bioparticles with scaffold envelope structures, but devoid material. Both EVs VLPs deliver ribonucleoprotein cargo target cytoplasm, ensuring machinery is only transiently active thereby increasing its safety. In review, we explore natural diversity their potential delivery clustered regularly interspaced short palindromic repeats (CRISPR) machinery. We illustrate different strategies optimization CDV loading retargeting, highlighting versatility tunability these vehicles. Nonetheless, lack robust standardized protocols production, purification, quality assessment still hinders widespread adoption further CRISPR-based therapies advanced "living drugs." believe collective, multifaceted effort urgently needed address critical issues unlock full genome-editing technologies yield safe, easy-to-manufacture, pharmacologically well-defined therapies. Finally, discuss current clinical landscape lung-directed cystic fibrosis could drive significant breakthroughs vivo disease.

Language: Английский

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Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators

Molecular and Cellular Pediatrics, Journal Year: 2025, Volume and Issue: 12(1)

Published: May 5, 2025

Abstract Background Cystic fibrosis (CF) is a systemic disorder of exocrine glands that caused by mutations in the CFTR gene. Main body The basic defect people with CF (pwCF) leads to impaired epithelial transport chloride and bicarbonate can be assessed biomarkers, i.e. β-adrenergic sweat rate concentration (SCC), conductance nasal respiratory epithelium (NPD), urine secretion bicarbonate, intestinal current measurements (ICM) secretory responses rectal biopsies bioassays organoids or cell cultures. modulators are novel class drugs improve defective posttranslational processing, trafficking function mutant CFTR. By April 2025, triple combination therapy potentiator ivacaftor (IVA) correctors elexacaftor (ELX) tezacaftor (TEZ) has been approved Europe for treatment all pwCF who do not carry two minimal mutations. Previous phase 3 post-approval 4 studies harbour one alleles major mutation F508del consistently reported significant improvements lung anthropometry upon initiation ELX/TEZ/IVA compared baseline. Normalization SCC, NPD ICM correlated clinical outcomes on population level, but restoration was diverse predictive outcome individual patient. Theratyping non-F508del genotypes patient-derived cultures revealed most cases clinically meaningful increases activity exposure ELX/TEZ/IVA. Likewise, every second patient improved SCC indicating modulator potentially beneficial This group eligible may opt gene addition future, as first-in-human trial recombinant lentiviral vector underway. Future directions upcoming generation will probably experience rather normal life childhood adolescence. To classify personal signatures disease times efficient modulators, we need more sensitive biomarkers address long-term course airway gut microbiome, host defense, homeostasis multiorgan metabolism.

Language: Английский

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