Molecular Therapy. Nucleic Acids最新文献_第8页

Guidelines for mitochondrial RNA analysis 线粒体 RNA 分析指南

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-26 DOI: 10.1016/j.omtn.2024.102262

Amela Jusic, Zoi Erpapazoglou, Louise Torp Dalgaard, Païvi Lakkisto, David de Gonzalo Calvo, Bettina Benczik, Bence Ágg, Péter Ferdinandy, Katarzyna Fiedorowicz, Blanche Schroen, Antigone Lazou, Yvan Devaux, on behalf of EU-CardioRNA COST Action CA17129, AtheroNET COST Action CA21153

{"title":"Guidelines for mitochondrial RNA analysis","authors":"Amela Jusic, Zoi Erpapazoglou, Louise Torp Dalgaard, Païvi Lakkisto, David de Gonzalo Calvo, Bettina Benczik, Bence Ágg, Péter Ferdinandy, Katarzyna Fiedorowicz, Blanche Schroen, Antigone Lazou, Yvan Devaux, on behalf of EU-CardioRNA COST Action CA17129, AtheroNET COST Action CA21153","doi":"10.1016/j.omtn.2024.102262","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102262","url":null,"abstract":"Mitochondria are the energy-producing organelles of mammalian cells with critical involvement in metabolism and signaling. Studying their regulation in pathological conditions may lead to the discovery of novel drugs to treat, for instance, cardiovascular or neurological diseases, which affect high-energy-consuming cells such as cardiomyocytes, hepatocytes, or neurons. Mitochondria possess both protein-coding and noncoding RNAs, such as microRNAs, long noncoding RNAs, circular RNAs, and piwi-interacting RNAs, encoded by the mitochondria or the nuclear genome. Mitochondrial RNAs are involved in anterograde-retrograde communication between the nucleus and mitochondria and play an important role in physiological and pathological conditions. Despite accumulating evidence on the presence and biogenesis of mitochondrial RNAs, their study continues to pose significant challenges. Currently, there are no standardized protocols and guidelines to conduct deep functional characterization and expression profiling of mitochondrial RNAs. To overcome major obstacles in this emerging field, the EU-CardioRNA and AtheroNET COST Action networks summarize currently available techniques and emphasize critical points that may constitute sources of variability and explain discrepancies between published results. Standardized methods and adherence to guidelines to quantify and study mitochondrial RNAs in normal and disease states will improve research outputs, their reproducibility, and translation potential to clinical application.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"487 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing natural killer cells proliferation and cytotoxicity using imidazole-based lipid nanoparticles encapsulating interleukin-2 mRNA 利用包裹白细胞介素-2 mRNA 的咪唑基脂质纳米颗粒增强自然杀伤细胞的增殖和细胞毒性

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-26 DOI: 10.1016/j.omtn.2024.102263

Christophe Delehedde, Ivan Ciganek, Pierre Louis Bernard, Nabila Laroui, Cathy Costa Da Silva, Cristine Gonçalves, Jacques Nunes, Anne-Lise Bennaceur-Griscelli, Jusuf Imeri, Matthias Huyghe, Luc Even, Patrick Midoux, Nathalie Rameix, Geoffrey Guittard, Chantal Pichon

{"title":"Enhancing natural killer cells proliferation and cytotoxicity using imidazole-based lipid nanoparticles encapsulating interleukin-2 mRNA","authors":"Christophe Delehedde, Ivan Ciganek, Pierre Louis Bernard, Nabila Laroui, Cathy Costa Da Silva, Cristine Gonçalves, Jacques Nunes, Anne-Lise Bennaceur-Griscelli, Jusuf Imeri, Matthias Huyghe, Luc Even, Patrick Midoux, Nathalie Rameix, Geoffrey Guittard, Chantal Pichon","doi":"10.1016/j.omtn.2024.102263","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102263","url":null,"abstract":"mRNA applications have undergone unprecedented applications—from vaccination to cell therapy. Natural killer (NK) cells are recognized to have a significant potential in immunotherapy. NK-based cell therapy has drawn attention as allogenic graft with a minimal graft-versus-host risk leading to easier off-the-shelf production. NK cells can be engineered with either viral vectors or electroporation, involving high costs, risks, and toxicity, emphasizing the need for alternative way as mRNA technology. We successfully developed, screened, and optimized novel lipid-based platforms based on imidazole lipids. Formulations are produced by microfluidic mixing and exhibit a size of approximately 100 nm with a polydispersity index of less than 0.2. They are able to transfect NK-92 cells, KHYG-1 cells, and primary NK cells with high efficiency without cytotoxicity, while Lipofectamine Messenger Max and D-Lin-MC3 lipid nanoparticle-based formulations do not. Moreover, the translation of non-modified mRNA was higher and more stable in time compared with a modified one. Remarkably, the delivery of therapeutically relevant interleukin 2 mRNA resulted in extended viability together with preserved activation markers and cytotoxic ability of both NK cell lines and primary NK cells. Altogether, our platforms feature all prerequisites needed for the successful deployment of an NK-based therapeutic strategies.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"11 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Harnessing mRNA to unleash endolysins: A new frontier in antibacterial therapy. 利用 mRNA 释放内溶酶：抗菌疗法的新领域

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-26 eCollection Date: 2024-09-10 DOI: 10.1016/j.omtn.2024.102249

Daniel C Nelson, Urmil M Dave, Norberto Gonzalez-Juarbe

引用次数: 0

Circular RNA-based therapy provides sustained and robust neuroprotection for retinal ganglion cells 基于环形 RNA 的疗法可为视网膜神经节细胞提供持续、稳健的神经保护

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102258

Wenbing Jiang, Dongchang Xiao, Cheng Wu, Jiaqi Yang, Xinghua Peng, Linfeng Chen, Jiamin Zhang, Gaofeng Zha, Wei Li, Rong Ju, Mengqing Xiang, Zhi Xie

{"title":"Circular RNA-based therapy provides sustained and robust neuroprotection for retinal ganglion cells","authors":"Wenbing Jiang, Dongchang Xiao, Cheng Wu, Jiaqi Yang, Xinghua Peng, Linfeng Chen, Jiamin Zhang, Gaofeng Zha, Wei Li, Rong Ju, Mengqing Xiang, Zhi Xie","doi":"10.1016/j.omtn.2024.102258","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102258","url":null,"abstract":"Ocular neurodegenerative diseases like glaucoma lead to progressive retinal ganglion cell (RGC) loss, causing irreversible vision impairment. Neuroprotection is needed to preserve RGCs across debilitating conditions. Nerve growth factor (NGF) protein therapy shows efficacy, but struggles with limited bioavailability and a short half-life. Here we explore a novel approach to address this deficiency by utilizing circular RNA (circRNA)-based therapy. We show that circRNAs exhibit an exceptional capacity for prolonged protein expression and circRNA-expressed NGF protects cells from glucose deprivation. In a mouse optic nerve crush model, lipid nanoparticle (LNP)-formulated circNGF administered intravitreally protects RGCs and axons from injury-induced degeneration. It also significantly outperforms NGF protein therapy without detectable retinal toxicity. Furthermore, single-cell transcriptomics revealed LNP-circNGF’s multifaceted therapeutic effects, enhancing genes related to visual perception while reducing trauma-associated changes. This study signifies the promise of circRNA-based therapies for treating ocular neurodegenerative diseases and provides an innovative intervention platform for other ocular diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"49 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional benefit of CRISPR-Cas9-induced allele deletion for RYR1 dominant mutation CRISPR-Cas9诱导等位基因缺失对RYR1显性突变的功能益处

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102259

Mathilde Beaufils, Margaux Melka, Julie Brocard, Clement Benoit, Nagi Debbah, Kamel Mamchaoui, Norma B. Romero, Anne Frédérique Dalmas-Laurent, Susana Quijano-Roy, Julien Fauré, John Rendu, Isabelle Marty

{"title":"Functional benefit of CRISPR-Cas9-induced allele deletion for RYR1 dominant mutation","authors":"Mathilde Beaufils, Margaux Melka, Julie Brocard, Clement Benoit, Nagi Debbah, Kamel Mamchaoui, Norma B. Romero, Anne Frédérique Dalmas-Laurent, Susana Quijano-Roy, Julien Fauré, John Rendu, Isabelle Marty","doi":"10.1016/j.omtn.2024.102259","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102259","url":null,"abstract":"More than 700 pathogenic or probably pathogenic variations have been identified in the gene causing various myopathies collectively known as “-related myopathies.” There is no treatment for these myopathies, and gene therapy stands out as one of the most promising approaches. In the context of a dominant form of central core disease due to a mutation, we aimed at showing the functional benefit of inactivating specifically the mutated allele by guiding CRISPR-Cas9 cleavages onto frequent single-nucleotide polymorphisms (SNPs) segregating on the same chromosome. Whole-genome sequencing was used to pinpoint SNPs localized on the mutant allele and identified specific CRISPR-Cas9 guide RNAs. Lentiviruses encoding these guide RNAs and the nuclease were used to transduce immortalized patient myoblasts, inducing the specific deletion of the mutant allele. The efficiency of the deletion was assessed at DNA and RNA levels, and at the functional level after monitoring calcium release induced by the stimulation of the RyR1-channel. This study provides proof of concept regarding the benefits of mutant allele deletion, in the case of a dominant mutation, from both a molecular and functional perspective, and could apply potentially to 20% of all patients with a mutation.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"27 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancing cancer treatments: The role of oligonucleotide-based therapies in driving progress 推进癌症治疗：基于寡核苷酸的疗法在推动进展中的作用

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102256

Bogdan Dume, Emilia Licarete, Manuela Banciu

{"title":"Advancing cancer treatments: The role of oligonucleotide-based therapies in driving progress","authors":"Bogdan Dume, Emilia Licarete, Manuela Banciu","doi":"10.1016/j.omtn.2024.102256","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102256","url":null,"abstract":"Although recent advancements in cancer immunology have resulted in the approval of numerous immunotherapies, minimal progress has been observed in addressing hard-to-treat cancers. In this context, therapeutic oligonucleotides, including interfering RNAs, antisense oligonucleotides, aptamers, and DNAzymes, have gained a central role in cancer therapeutic approaches due to their capacity to regulate gene expression and protein function with reduced toxicity compared with conventional chemotherapeutics. Nevertheless, systemic administration of naked oligonucleotides faces many extra- and intracellular challenges that can be overcome by using effective delivery systems. Thus, viral and non-viral carriers can improve oligonucleotide stability and intracellular uptake, enhance tumor accumulation, and increase the probability of endosomal escape while minimizing other adverse effects. Therefore, gaining more insight into fundamental mechanisms of actions of various oligonucleotides and the challenges posed by naked oligonucleotide administration, this article provides a comprehensive review of the recent progress on oligonucleotide delivery systems and an overview of completed and ongoing cancer clinical trials that can shape future oncological treatments.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"53 98 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential network analysis reveals the key role of the ECM-receptor pathway in α-particle-induced malignant transformation 差异网络分析揭示了 ECM-受体通路在α粒子诱导的恶性转化中的关键作用

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102260

Wenying Yan, Wentao Hu, Yidan Song, Xingyi Liu, Ziyun Zhou, Wanshi Li, Zhifei Cao, Weiwei Pei, Guangming Zhou, Guang Hu

{"title":"Differential network analysis reveals the key role of the ECM-receptor pathway in α-particle-induced malignant transformation","authors":"Wenying Yan, Wentao Hu, Yidan Song, Xingyi Liu, Ziyun Zhou, Wanshi Li, Zhifei Cao, Weiwei Pei, Guangming Zhou, Guang Hu","doi":"10.1016/j.omtn.2024.102260","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102260","url":null,"abstract":"Space particle radiation is a major environmental factor in spaceflight, and it is known to cause body damage and even trigger cancer, but with unknown molecular etiologies. To examine these causes, we developed a systems biology approach by focusing on the co-expression network analysis of transcriptomics profiles obtained from single high-dose (SE) and multiple low-dose (ME) -particle radiation exposures of BEAS-2B human bronchial epithelial cells. First, the differential network and pathway analysis based on the global network and the core modules showed that genes in the ME group had higher enrichment for the extracellular matrix (ECM)-receptor interaction pathway. Then, collagen gene COL1A1 was screened as an important gene in the ME group assessed by network parameters and an expression study of lung adenocarcinoma samples. COL1A1 was found to promote the emergence of the neoplastic characteristics of BEAS-2B cells by both experimental analyses and immunohistochemical staining. These findings suggested that the degree of malignant transformation of cells in the ME group was greater than that of the SE, which may be caused by the dysregulation of the ECM-receptor pathway.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"364 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Boosting DNA vaccine power by lipid nanoparticles surface engineered with amphiphilic bioresorbable copolymer 用两亲性生物可吸收共聚物对脂质纳米粒子进行表面工程处理，增强 DNA 疫苗的威力

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102261

Chung-Hsiang Yang, Kuan-Yin Shen, Hui-Min Ho, Chiung-Yi Huang, Yu-Jhen Cheng, Chih-Chun Pu, Fang-Feng Chiu, Wan-Chun Huang, Hung-Chun Liao, Hsin-Wei Chen, Ching-Len Liao, Shih-Jen Liu, Ming-Hsi Huang

{"title":"Boosting DNA vaccine power by lipid nanoparticles surface engineered with amphiphilic bioresorbable copolymer","authors":"Chung-Hsiang Yang, Kuan-Yin Shen, Hui-Min Ho, Chiung-Yi Huang, Yu-Jhen Cheng, Chih-Chun Pu, Fang-Feng Chiu, Wan-Chun Huang, Hung-Chun Liao, Hsin-Wei Chen, Ching-Len Liao, Shih-Jen Liu, Ming-Hsi Huang","doi":"10.1016/j.omtn.2024.102261","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102261","url":null,"abstract":"Successful DNA vaccination generally requires the aid of either a viral vector within vaccine components or an electroporation device into the muscle or skin of the host. However, these systems come with certain obstacles, including limited transgene capacity, broad preexisting immunity in humans, and substantial cell death caused by high voltage pulses, respectively. In this study, we repurposed the use of an amphiphilic bioresorbable copolymer (ABC), called PLA-PEG, as a surface engineering agent that conciliates lipid nanoparticles (LNPs) between stability during preparation and biocompatibility post-vaccination. The LNP carrier can be loaded with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific DNA; in this form, the DNA-LNP is immunogenic in hamsters and elicits protective immunity following DNA-LNP vaccination against heterologous virus challenge or as a hybrid-type vaccine booster against SARS-CoV-2 variants. The data provide comprehensive information on the relationships between LNP composition, manufacturing process, and vaccine efficacy. The outcomes of this study offer new insights into designing next-generation LNP formulations and pave the way for boosting vaccine power to combat existing and possible emerging infectious diseases/pathogens.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"9 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Topical application of a CCL22-binding aptamer suppresses contact allergy 局部应用与 CCL22 结合的适配体能抑制接触性过敏

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102254

Anna Jonczyk, Marlene Gottschalk, Matthew S.J. Mangan, Yasmin Majlesain, Manja W. Thiem, Lea-Corinna Burbaum, Heike Weighardt, Eicke Latz, Günter Mayer, Irmgard Förster

{"title":"Topical application of a CCL22-binding aptamer suppresses contact allergy","authors":"Anna Jonczyk, Marlene Gottschalk, Matthew S.J. Mangan, Yasmin Majlesain, Manja W. Thiem, Lea-Corinna Burbaum, Heike Weighardt, Eicke Latz, Günter Mayer, Irmgard Förster","doi":"10.1016/j.omtn.2024.102254","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102254","url":null,"abstract":"Allergic contact dermatitis is a prevalent occupational disease with limited therapeutic options. The chemokine CCL22, a ligand of the chemokine receptor CCR4, directs the migration of immune cells. Here, it is shown that genetic deficiency of CCL22 effectively ameliorated allergic reactions in contact hypersensitivity (CHS), a commonly used mouse model of allergic contact dermatitis. For the pharmacological inhibition of CCL22, DNA aptamers specific for murine CCL22 were generated by the systematic evolution of ligands by exponential enrichment (SELEX). Nine CCL22-binding aptamers were initially selected and functionally tested . The 29-nt DNA aptamer AJ102.29m profoundly inhibited CCL22-dependent T cell migration and did not elicit undesired Toll-like receptor-dependent immune activation. AJ102.29m efficiently ameliorated CHS after systemic application. Moreover, CHS-associated allergic symptoms were also reduced following topical application of the aptamer on the skin. Microscopic analysis of skin treated with AJ102.29m demonstrated that the aptamer could penetrate into the epidermis and dermis. The finding that epicutaneous application of the aptamer AJ102.29m in a cream was as effective in suppressing the allergic reaction as intraperitoneal injection paves the way for therapeutic use of aptamers beyond the current routes of systemic administration.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"157 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141507339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function 发现 SSBP1 的新型致病突变，并利用腺嘌呤碱基编辑器对其进行校正以改善线粒体功能

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-17 DOI: 10.1016/j.omtn.2024.102257

Ju Hyuen Cha, Seok-Hoon Lee, Yejin Yun, Won Hoon Choi, Hansol Koo, Sung Ho Jung, Ho Byung Chae, Dae Hee Lee, Seok Jae Lee, Dong Hyun Jo, Jeong Hun Kim, Jae-Jin Song, Jong-Hee Chae, Jun Ho Lee, Jiho Park, Jin Young Kang, Sangsu Bae, Sang-Yeon Lee

{"title":"Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function","authors":"Ju Hyuen Cha, Seok-Hoon Lee, Yejin Yun, Won Hoon Choi, Hansol Koo, Sung Ho Jung, Ho Byung Chae, Dae Hee Lee, Seok Jae Lee, Dong Hyun Jo, Jeong Hun Kim, Jae-Jin Song, Jong-Hee Chae, Jun Ho Lee, Jiho Park, Jin Young Kang, Sangsu Bae, Sang-Yeon Lee","doi":"10.1016/j.omtn.2024.102257","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102257","url":null,"abstract":"Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with mutations.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"9 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0