Molecular Therapy. Nucleic Acids最新文献

{"title":"Impact on efficacy of target reduction of two FDA-approved ASO drugs by intracellular glucose levels in <i>in vitro</i> cell models.","authors":"Le Tra Giang Nguyen, Sherouk M Tawfik, Jing Jin, Andrea Durwin, Xiao-Bo Zhong","doi":"10.1016/j.omtn.2025.102487","DOIUrl":"10.1016/j.omtn.2025.102487","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) have emerged as a new therapeutic modality for the treatment of both rare and common human diseases. A significant proportion of the patient population that may benefit from ASO therapy may also have common diseases, such as diabetes mellitus. The potential influence of prevalent diseases on the effectiveness of ASO drugs in silencing their target mRNAs remains largely unexplored. The present study utilized <i>in vitro</i> cell models to determine the impact on the efficacy of target reduction of two US Food and Drug Administration (FDA)-approved ASO drugs by intracellular glucose levels. Using inotersen and mipomersen as the FDA-approved ASO model drugs, this study demonstrated that a higher intracellular level of glucose resulted in decreased silencing efficacy of target reduction of inotersen and mipomersen in HepG2 cells. Reducing intracellular glucose levels in HepG2 cells, either by knocking down the glucose transporter GLUT2 or by treating with the antidiabetic drug metformin, reversed the decreased silencing efficacy of inotersen and mipomersen. This study brings to light the first indication about the significant impact of intracellular glucose levels on the silencing efficacy of the FDA-approved ASO drugs in an <i>in vitro</i> model.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102487"},"PeriodicalIF":6.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies.","authors":"Laura Siles, Esther Pomares","doi":"10.1016/j.omtn.2025.102482","DOIUrl":"10.1016/j.omtn.2025.102482","url":null,"abstract":"<p><p>Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa and Stargardt disease, are a group of rare diseases caused by mutations in more than 300 genes that currently have no treatment in most cases. They commonly trigger blindness and other ocular affectations due to retinal cell degeneration. Gene editing has emerged as a promising and powerful strategy for the development of IRD therapies, allowing the permanent correction of pathogenic variants. Using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and transcription activator-like effector nucleases (TALEN) gene-editing tools, we precisely corrected seven hiPS cell lines derived from IRD patients carrying mutations in <i>ABCA4</i>, <i>BEST1</i>, <i>PDE6A</i>, <i>PDE6C</i>, <i>RHO,</i> or <i>USH2A</i>. Homozygous mutations and point insertions/deletions resulted in the highest homology-directed repair efficiencies, with at least half of the clones repaired properly without off-target effects. Strikingly, correction of a heterozygous pathogenic variant was achieved using the wild-type allele of the patient as the template for DNA repair. These results suggest the unexpected potential application of CRISPR as a donor template-free strategy for single-nucleotide modifications. Additionally, the corrected clones exhibited a reversion of the disease-associated phenotype in retinal cellular models. These data strengthen the study and application of gene editing-based approaches for IRD treatment.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102482"},"PeriodicalIF":6.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Albumin-conjugation enables improved tumor targeting of aptamers via SPECT imaging.","authors":"Shaowen Yang, Chengwen Zheng, Sixuan Cheng, Li Wen, Pinghui Li, Jianbo Li, Xiaoli Lan, Dawei Jiang","doi":"10.1016/j.omtn.2025.102483","DOIUrl":"10.1016/j.omtn.2025.102483","url":null,"abstract":"<p><p>Aptamers are single-stranded oligonucleotides with specific spatial structures. They have been widely used in preclinical studies because of their high affinity and specificity for various biological targets. AS1411, an aptamer targeting the nucleolin overexpressed on the cancer cell membrane, is one of the most promising and extensively studied aptamers. However, extremely low bioavailability due to rapid renal excretion remains a great obstacle for aptamers' clinical translation. Human serum albumin (HSA), with long blood circulation and excellent biocompatibility, has been an attractive vehicle for extending drugs' blood half-life in the clinic. This work investigated the effect of an albumin-conjugated strategy in improving aptamers' tumor targeting <i>in vivo</i> for the first time by taking AS1411 as an example. HSA-AS1411 was synthesized via the maleimide-sulfhydryl reaction. The excellent serum stability and maintained target affinity of HSA-AS1411 were demonstrated <i>in vitro</i>. The pharmacokinetic analysis and tumor SPECT imaging studies revealed that HSA-AS1411 had over 14 times longer circulation half-life and superior tumor uptake than those of AS1411. The immunofluorescence staining of tumor tissues further indicated the improved tumor retention of AS1411 as a result of prolonged blood circulation. Therefore, the HSA-conjugated strategy has a promising prospect in improving aptamers' tumor targeting for clinical applications.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102483"},"PeriodicalIF":6.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A combination of systemic mannitol and mannitol modified polyester nanoparticles for caveolae-mediated gene delivery to the brain.","authors":"Betsy Reshma Gilbert, Chirag Miglani, Arundhati Karmakar, Muneesh Pal, Vysakh C Chandran, Sarika Gupta, Asish Pal, Munia Ganguli","doi":"10.1016/j.omtn.2025.102480","DOIUrl":"10.1016/j.omtn.2025.102480","url":null,"abstract":"<p><p>Overcoming the blood-brain barrier (BBB) remains a significant challenge for nucleic acid delivery to the brain. We have explored a combination of mannitol-modified poly (β-amino ester) (PBAE) nanoparticles and systemic mannitol injection for crossing the BBB. We incorporated mannitol in the PBAE polymer for caveolae targeting and selected monomers that may help avoid delivery to the liver. We also induced caveolae at the BBB through systemic mannitol injection in order to create an opportunity for the caveolae-targeting nanoparticles (M30 D90) containing plasmid DNA to cross the BBB. When a clinically relevant dose was administered intravenously in this caveolae induction model, M30 D90 demonstrated significant transgene expression of a reporter plasmid in the brain, with selective uptake by neuronal cells and minimal liver accumulation. We demonstrate that caveolae modulation using systemic mannitol administration and caveolae targeting using designed nanoparticles are necessary for efficient delivery to the brain. This delivery platform offers a simple, scalable, and controlled delivery solution and holds promise for treating brain diseases with functional targets.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102480"},"PeriodicalIF":6.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.","authors":"Sandra Smieszek, Bartlomiej Przychodzen, Christina Tyner, Caroline Johnson, Haimeng Bai, Jennifer M Kwon, D Walker Hagan, Caitlyn Niccum, Rocky Brighton, Kenneth Hawkins, Romy Aiken, Ahmad Nawaz, Xiufang Guo, James Hickman, Christos M Polymeropoulos, Gunther Birznieks, Mihael H Polymeropoulos","doi":"10.1016/j.omtn.2025.102479","DOIUrl":"10.1016/j.omtn.2025.102479","url":null,"abstract":"<p><p>Immunoglobulin mu-binding protein 2 (<i>IGHMBP2</i>) pathogenic variants lead to a spectrum of disorders characterized by alpha-motor neuron degeneration. We describe a compound heterozygous patient diagnosed with Charcot-Marie-Tooth disease type 2S with variants in <i>IGHMBP2</i>: a pathogenic missense variant acting in <i>trans</i> with a confirmed intronic cryptic splice site variant. This variant was shown to result in the creation of a new splice acceptor site, loss of reading frame and nonsense-mediated decay. We designed a 19-mer antisense oligonucleotide targeting this cryptic intronic variant to restore IGHMBP2 levels. ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels. Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses. Furthermore, toxicity testing revealed that intrathecal administration of the ASO to wild-type Sprague-Dawley rats over 3 months was well tolerated. Our preclinical data support this ASO as a potential CMT2S treatment by rescuing IGHMBP2. N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102479"},"PeriodicalIF":6.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.","authors":"Taryn Diep, Wesley Zhou, Rachel E Reyes, Matthew Nitzahn, Isabel L Day, Georgios Makris, Lindsay Lueptow, Irina Zhuravka, Stuti Bakshi, Jon Gangoiti, Hyacinth Padaon, Yunfeng Li, Bruce A Barshop, Johannes Haberle, Gerald S Lipshutz","doi":"10.1016/j.omtn.2025.102470","DOIUrl":"10.1016/j.omtn.2025.102470","url":null,"abstract":"<p><p>Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea-cycle disorder, results in hyperammonemia initiating a sequence of adverse events that can lead to coma and death if not treated rapidly. There is a high unmet need for an effective therapeutic for this disorder, especially in early neonatal patients where mortality is excessive. However, development of an adeno-associated virus (AAV)-based approach is hampered by large cDNA size and high protein requirement. We developed an oversized AAV vector as a gene therapy to treat <i>CPS1</i> deficiency. In order to constrain genome size, we utilized small liver-specific promoter/enhancers and a minimal polyadenylation signal. Long-term survival (9 months, end of study) with ammonia control was achieved in AAV8.CPS1-administered Cps1^flox/flox mice, while all null vector-injected controls died with marked hyperammonemia; female mice demonstrated improved survival over treated males. While glutamine remained elevated compared to controls, ammonia was controlled in surviving animals. Mice maintained their weights and were not sarcopenic. While drinking water did contain carglumic acid, no nitrogen scavengers were administered. Although there were concerns with vector genomic integrity, these findings demonstrate proof of concept for an oversized gene-therapy approach for a challenging urea-cycle disorder where high-level hepatic protein is essential for survival.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102470"},"PeriodicalIF":6.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"piRNA/PIWI pathways and epigenetic crosstalk in human diseases: Molecular insights into HIV-1 infection and drugs of abuse.","authors":"Karthick Chennakesavan, James Haorah, Thangavel Samikkannu","doi":"10.1016/j.omtn.2025.102473","DOIUrl":"10.1016/j.omtn.2025.102473","url":null,"abstract":"<p><p>P-element-induced wimpy (PIWI)-interacting RNAs (piRNAs) and PIWI proteins have long been studied in insects and germline cells for their roles in regulating transposable elements (TEs). However, emerging evidence suggests that piRNAs and PIWI proteins also play crucial roles in human diseases beyond gametocyte protection, and these molecules are implicated in the onset and progression of various human diseases, particularly those arising in somatic cells. Notably, piRNAs and PIWI proteins are increasingly recognized for their involvement in cancers, cardiovascular diseases, neurodegenerative disorders, and viral infections, including HIV. This review first provides an overview of piRNAs/PIWIs and their interactions with TEs and primary targets. We then explore the molecular mechanisms and signaling pathways through which piRNAs and PIWIs modulate human disease processes, focusing on neurodegeneration, cancers, and HIV. Special attention is given to the role of piRNA/PIWI complexes in regulating gene transcription, translation, and post-translational modifications in the context of disease. Additionally, we address emerging research into the role of piRNAs/PIWIs in HIV- and drug abuse or substance abuse-associated neurodegenerative diseases, highlighting existing knowledge gaps. Finally, we discuss future research directions to understand better the functions of piRNAs/PIWI proteins in human health and disease.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102473"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive detection of allele-specific CRISPR-SaCas9-KKH disruption of <i>TOR1A</i> DYT1 allele in a xenograft mouse model.","authors":"Katia E Maalouf, Dawn Madison Frederick, Nutan Sharma, Edwina Abou Haidar, Tianhe Xiao, Justin Seungkyu Han, Mohammed S Mahamdeh, Roy J Soberman, David Rufino-Ramos, Benjamin P Kleinstiver, Hyder A Jinnah, Christine A Vaine, D Cristopher Bragg, Koen Breyne","doi":"10.1016/j.omtn.2025.102466","DOIUrl":"10.1016/j.omtn.2025.102466","url":null,"abstract":"<p><p>DYT1 dystonia is a neurological movement disorder characterized by a dominant 3-base pair deletion (ΔGAG) in the <i>TOR1A</i> gene. This study demonstrates a gene-editing approach that selectively targets the ΔGAG mutation in the <i>TOR1A</i> DYT1 allele while safeguarding the wild-type (WT) <i>TOR1A</i> allele. We optimized an adeno-associated virus (AAV) vector-compatible variant of the <i>Staphylococcus aureus</i> Cas9 nuclease ortholog (SaCas9-KKH) in DYT1 patient-derived human neuronal progenitor cells (hNPCs). On-target editing of the <i>TOR1A</i> DYT1 allele was confirmed at the genomic level from brain tissue in a xenograft mouse model. To avoid brain biopsy for demonstrating <i>TOR1A</i> DYT1 editing, we developed a non-invasive monitoring method using extracellular RNA (exRNA). <i>TOR1A</i> exRNA was retrieved from the extracellular vesicle (EV) secretions of hNPCs and plasma samples, indicating whether the donor was a <i>TOR1A</i> DYT1 carrier. This technique enabled us to assess AAV-mediated disruption of the <i>TOR1A</i> DYT1 allele in the brains of mice using blood samples.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102466"},"PeriodicalIF":6.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations.","authors":"Lucas Tricoli, Sunetra Sase, Julia L Hacker, Vi Pham, Maxwell Chappell, Laura Breda, Stephanie N Hurwitz, Naoto Tanaka, Carlo Castruccio Castracani, Amaliris Guerra, Zhongqi Hou, Lars Schlotawa, Karthikeyan Radhakrishnan, Matthew Hogenauer, Aoife Roche, John Everett, Frederic Bushman, Peter Kurre, Rebecca Ahrens-Nicklas, Laura A Adang, Adeline L Vanderver, Stefano Rivella","doi":"10.1016/j.omtn.2025.102464","DOIUrl":"10.1016/j.omtn.2025.102464","url":null,"abstract":"<p><p>Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplantion (HSCT) with lentiviral (LV)-based gene therapy has great potential to treat MLD. Achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low vector copy number (VCN) is crucial. Insufficient enzyme levels can lead to the progression of motor symptoms, undermining treatment goals. Conversely, elevated VCN increases the risk of genotoxicity, which poses safety concerns, and contributes to higher production costs, making the therapy less accessible. Striking this balance is essential to maximize clinical benefit while minimizing risks and costs. To address this need, we increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human hematopoietic stem cells (HSCs) with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4× more ARSA activity than the currently US and European Union (EU)-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-old <i>Arsa</i>-knockout (KO) MLD mice transplanted with <i>Arsa</i>-KO bone marrow (BM) cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching wild-type (WT) mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating MLD patients.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102464"},"PeriodicalIF":6.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ratio of miRNA-29 to miRNA-199 expression coordinates mesenchymal stem cell repair of bleomycin-induced pulmonary injury.","authors":"Sharon J Elliot, Dustin Anderson-Terhune, Benjamin Roos, Gustavo A Rubio, Xiaomei Xia, Simone Pereira-Simon, Paola Catanuto, Gina Civettini, Emily S Hagen, Constadina Arvanitis, Shahriar Shahzeidi, Marilyn K Glassberg","doi":"10.1016/j.omtn.2025.102461","DOIUrl":"10.1016/j.omtn.2025.102461","url":null,"abstract":"<p><p>Our previous work demonstrated the anti-fibrotic effects of infusion of adipose-derived mesenchymal stem cells (ASCs) to prevent or repair bleomycin (BLM)-induced lung injury. The present study investigates mechanisms driving these anti-fibrotic effects. Pulmonary fibrosis developed at day 12 in 22-month-old C57BL/6 male mice after intratracheal BLM instillation. There was a decrease in indices of pulmonary fibrosis, including collagen content, AKT activation, collagen types I and III, α_V-integrin, tumor necrosis factor alpha, and transforming growth factor β mRNA after infusion of ASCs 12 days post-BLM treatment compared to BLM alone. Infusion of ASCs increased the population of alveolar types I and II epithelial cells that had been reduced after BLM treatment. miRNAscope technology and reverse-transcription polymerase chain reaction revealed that ASC-treated mice demonstrated increased miR-29a, decreased miR-199, and increased telomere length, telomerase RNA component, and telomerase reverse transcriptase compared to BLM alone. <i>In vitro</i> and <i>ex vivo</i> experiments using double-transfected mouse or human myofibroblasts (miR-29 mimic, and miR-199 inhibitor) confirmed that alterations of these miRNAs regulate downstream effectors of fibrosis. These data suggest that alteration of the ratio of anti-fibrotic to fibrotic miRNAs and increase in telomere length are critical mechanisms of ASC-mediated repair of BLM-induced pulmonary fibrosis.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102461"},"PeriodicalIF":6.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}