Human gene therapy最新文献

{"title":"Unconstrained Precision Mitochondrial Genome Editing with αDdCBEs.","authors":"Santiago R Castillo, Brandon W Simone, Karl J Clark, Patricia Devaux, Stephen C Ekker","doi":"10.1089/hum.2024.073","DOIUrl":"10.1089/hum.2024.073","url":null,"abstract":"<p><p>DddA-derived cytosine base editors (DdCBEs) enable the targeted introduction of C•G-to-T•A conversions in mitochondrial DNA (mtDNA). DdCBEs work in pairs, with each arm composed of a transcription activator-like effector (TALE), a split double-stranded DNA deaminase half, and a uracil glycosylase inhibitor. This pioneering technology has helped improve our understanding of cellular processes involving mtDNA and has paved the way for the development of models and therapies for genetic disorders caused by pathogenic mtDNA variants. Nonetheless, given the intrinsic properties of TALE proteins, several target sites in human mtDNA are predicted to remain out of reach to DdCBEs and other TALE-based technologies. Specifically, due to the conventional requirement for a thymine immediately upstream of the TALE target sequences (<i>i.e.</i>, the 5'-T constraint), over 150 loci in the human mitochondrial genome are presumed to be inaccessible to DdCBEs. Previous attempts at circumventing this requirement, either by developing monomeric DdCBEs or utilizing DNA-binding domains alternative to TALEs, have resulted in suboptimal specificity profiles with reduced therapeutic potential. Here, aiming to challenge and elucidate the relevance of the 5'-T constraint in the context of DdCBE-mediated mtDNA editing, and to expand the range of motifs that are editable by this technology, we generated DdCBEs containing TALE proteins engineered to recognize all 5' bases. These modified DdCBEs are herein referred to as αDdCBEs. Notably, 5'-T-noncompliant canonical DdCBEs efficiently edited mtDNA at diverse loci. However, they were frequently outperformed by αDdCBEs, which exhibited significant improvements in activity and specificity, regardless of the most 5' bases of their TALE binding sites. Furthermore, we showed that αDdCBEs are compatible with the enhanced DddA_tox variants DddA6 and DddA11, and we validated TALE shifting with αDdCBEs as an effective approach to optimize base editing outcomes. Overall, αDdCBEs enable efficient, specific, and unconstrained mitochondrial base editing.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"798-813"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142106920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Editing of the Endogenous Cryptic 3' Splice Site Corrects the RNA Splicing Defect in the β⁶⁵⁴-Thalassemia Mouse Model.","authors":"Dan Lu, Xiuli Gong, Xinbing Guo, Qin Cai, Yanwen Chen, Yiwen Zhu, Xiao Sang, Hua Yang, Miao Xu, Yitao Zeng, Dali Li, Fanyi Zeng","doi":"10.1089/hum.2023.202","DOIUrl":"10.1089/hum.2023.202","url":null,"abstract":"<p><p>β⁶⁵⁴-thalassemia is caused by a point mutation in the second intron (IVS-II) of the β-globin gene that activates a cryptic 3' splice site, leading to incorrect RNA splicing. Our previous study demonstrated that when direct deletion of the β⁶⁵⁴ mutation sequence or the cryptic 3' splice site in the IVS-II occurs, correct splicing of β-globin mRNA can be restored. Herein, we conducted an in-depth analysis to explore a more precise gene-editing method for treating β⁶⁵⁴-thalassemia. A single-base substitution of the cryptic 3' acceptor splice site was introduced in the genome of a β⁶⁵⁴-thalassemia mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9(Cas9)-mediated homology-directed repair (HDR). All of the HDR-edited mice allow the detection of correctly spliced β-globin mRNA. Pathological changes were improved compared with the nonedited β⁶⁵⁴ mice. This resulted in a more than twofold increase in the survival rate beyond the weaning age of the mice carrying the β⁶⁵⁴ allele. The therapeutic effects of this gene-editing strategy showed that the typical β-thalassemia phenotype can be improved in a dose-dependent manner when the frequency of HDR is over 20%. Our research provides a unique and effective method for correcting the splicing defect by gene editing the reactive splicing acceptor site in a β⁶⁵⁴ mouse model.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"825-837"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys.","authors":"Shun-Qing Liang, Andrew W Navia, Michelle Ramseier, Xuntao Zhou, Michele Martinez, Charles Lee, Chen Zhou, Joae Wu, Jun Xie, Qin Su, Dan Wang, Terence R Flotte, Daniel G Anderson, Alice F Tarantal, Alex K Shalek, Guangping Gao, Wen Xue","doi":"10.1089/hum.2024.035","DOIUrl":"10.1089/hum.2024.035","url":null,"abstract":"<p><p>Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping gene or a disease-related gene in the lungs of young rhesus monkeys. We observed up to 8% editing of <i>angiotensin-converting enzyme 2 (ACE2)</i> in lung lobes after single-dose administration. Single-nuclear RNA sequencing revealed that AAV5 transduces multiple cell types in the caudal lung lobes, including alveolar cells, macrophages, fibroblasts, endothelial cells, and B cells. These results demonstrate that AAV5 is efficient in the delivery of CRISPR/Cas9 in the lung lobes of young rhesus monkeys.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"814-824"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma.","authors":"Yi Zhou, Yongzhong Li, Jing Chenm, Kai Mei, Mingxiang Kang, Ping Chen, Qiu Li","doi":"10.1089/hum.2024.002","DOIUrl":"10.1089/hum.2024.002","url":null,"abstract":"<p><p>A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"838-854"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Coexpression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer.","authors":"Jason C Huang, Ming-Chun Li, I-Chieh Huang, Je-Ming Hu, Wei-Zhi Lin, Yu-Tien Chang","doi":"10.1089/hum.2023.207","DOIUrl":"10.1089/hum.2023.207","url":null,"abstract":"<p><p>Early diagnosis and intervention are pivotal in reducing colorectal cancer (CRC) incidence and enhancing patient outcomes. In this study, we focused on three genes, AQP8, GUCA2B, and SPIB, which exhibit high coexpression and play crucial roles in suppressing early-stage CRC. Our objective was to identify key miRNAs that can mitigate CRC tumorigenesis and modulate the coexpression network involving these genes. We conducted a comprehensive analysis using large-scale tissue mRNA data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus to validate the coexpression of AQP8, GUCA2B, and SPIB, and to assess their diagnostic and prognostic significance in CRC. The mRNA-miRNA interactions were examined using MiRNet and the Encyclopedia of RNA Interactomes. Furthermore, using various molecular techniques, we conducted miRNA inhibitor transfection experiments in HCT116 cells to evaluate their effects on cell growth, migration, and gene/protein expression. Our findings revealed that, compared with normal tissues, AQP8, GUCA2B, and SPIB exhibited high coexpression and were downregulated in CRC, particularly during tumorigenesis. OncoMirs, hsa-miR-182-5p, and hsa-miR-27a-3p, were predicted to regulate these genes. MiRNA inhibition experiments in HCT116 cells demonstrated the inhibitory effects of miR-27a-3p and miR-182-5p on GUCA2B mRNA and protein expression. These miRNAs promoted the proliferation of CRC cells, possibly through their involvement in the GUCA2B-GUCY2C axis, which is known to promote tumor growth. While the expressions of AQP8 and SPIB were barely detectable, their regulatory relationship with hsa-miR-182-5p remained inconclusive. Our study confirms that hsa-miR-27a-3p and hsa-miR-182-5p are oncomiRs in CRC. These miRNAs may contribute to GUCY2C dysregulation by downregulating GUCA2B, which encodes uroguanylin. Consequently, hsa-miR-182-5p and hsa-miR-27a-3p show promise as potential targets for early intervention and treatment in the early stages of CRC.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"855-867"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-Penetrating Peptides and CRISPR-Cas9: A Combined Strategy for Human Genetic Disease Therapy.","authors":"Carla Lira,Eduardo Mannarino Correia,Martin Bonamino,Zilton Farias Meira Vasconcelos","doi":"10.1089/hum.2024.020","DOIUrl":"https://doi.org/10.1089/hum.2024.020","url":null,"abstract":"The advent of Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated nuclease 9 (Cas9) technology has revolutionized the field of genetic engineering, offering unprecedented potential for the targeted manipulation of DNA sequences. Advances in the mechanism of action of the CRISPR-Cas9 system allowed potential applicability for the treatment of genetic diseases. CRISPR-Cas9's mechanism of action involves the use of an RNA guide molecule to target specific DNA sequences and the Cas9 enzyme to induce precise DNA cleavage. In the context of the CRISPR-Cas9 system, this review covers non-viral delivery methods for gene editing based on peptide internalization. Here we describe critical areas of discussion such as immunogenicity, emphasizing the importance of safety, efficiency, and cost-effectiveness, particularly in the context of treating single-mutation genetic diseases using advanced editing techniques genetics as prime editor and base editor. The text discusses the versatility of Cell-Penetrating Peptides (CPPs) in forming complexes for delivering biomolecules, particularly Ribonucleoprotein (RNP) for genome editing with CRISPR-Cas9 in human cells. In addition, it emphasizes the promise of combining CPPs with DNA base editing and prime editing systems. These systems, known for their simplicity and precision, hold great potential for correcting point mutations in human genetic diseases. In summary, the text provides a clear overview of the advantages of using CPPs for genome editing with CRISPR-Cas9, particularly in conjunction with advanced editing systems, highlighting their potential impact on clinical applications in the treatment of single-mutation genetic diseases.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"9 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adeno-Associated Virus Vectors-a Target of Cellular and Humoral Immunity-are Expanding Their Reach Toward Hematopoietic Stem Cell Modification and Immunotherapies.","authors":"Angela E Araujo, Martin Bentler, Xabier Perez Garmendia, Asma Kaleem, Claire Fabian, Michael Morgan, Ulrich T Hacker, Hildegard Büning","doi":"10.1089/hum.2024.114","DOIUrl":"10.1089/hum.2024.114","url":null,"abstract":"<p><p>All current market-approved gene therapy medical products for <i>in vivo</i> gene therapy of monogenic diseases rely on adeno-associated virus (AAV) vectors. Advances in gene editing technologies and vector engineering have expanded the spectrum of target cells and, thus, diseases that can be addressed. Consequently, AAV vectors are now being explored to modify cells of the hematopoietic system, including hematopoietic stem and progenitor cells (HSPCs), to develop novel strategies to treat monogenic diseases, but also to generate cell- and vaccine-based immunotherapies. However, the cell types that represent important new targets for the AAV vector system are centrally involved in immune responses against the vector and its transgene product as discussed briefly in the first part of this review. In the second part, studies exploring AAV vectors for genetic engineering of HSPCs, T and B lymphocytes, and beyond are presented.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"586-603"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpharetroviral Vector-Mediated Gene Therapy for IL7RA-Deficient Severe Combined Immunodeficiency.","authors":"Teng-Cheong Ha, Michael A Morgan, Adrian J Thrasher, Axel Schambach","doi":"10.1089/hum.2024.103","DOIUrl":"10.1089/hum.2024.103","url":null,"abstract":"<p><p>Severe combined immunodeficiency (SCID) encompasses rare primary immunodeficiency disorders characterized by deficient T-cell development, which leads to a severely compromised immune system and susceptibility to life-threatening infections. Among SCID subtypes, IL7RA-SCID is caused by mutations in the interleukin 7 receptor alpha chain (IL7RA) and represents a significant subset of patients with limited treatment options. This study investigated the efficacy of a self-inactivating (SIN) alpharetroviral vector (ARV) engineered to deliver a codon-optimized <i>IL7RA</i> cDNA to restore T-cell development in <i>Il7r</i>-knockout mice. We compared the elongation factor 1 alpha short (EFS) promoter and the lymphoid-restricted Lck promoter for their ability to drive IL7RA expression and found that the EFS promoter enabled robust and sustained IL7RA expression that led to the functional rescue of T-lymphopoiesis <i>in vitro</i> and <i>in vivo</i>. Conversely, though effective <i>in vitro</i>, the Lck promoter failed to produce viable T-cell populations <i>in vivo</i>. Our results highlight the potential of using SIN-ARVs as a gene therapy (GT) strategy for treating IL7RA-SCID. Importantly, sustained production of T-lymphocytes was found in both primary and secondary transplant recipient animals with no adverse effects, supporting the safety and feasibility of this approach. Overall, this study provides valuable insights into the development of GT for IL7RA-SCID and underscores the clinical potential of an EFS-driven SIN-ARV to restore IL7RA-deficient immune function.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"669-679"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Editing by Ferrying of CRISPR/Cas Ribonucleoprotein Complexes in Enveloped Virus-Derived Particles.","authors":"Jacob Hørlück Janns, Jacob Giehm Mikkelsen","doi":"10.1089/hum.2024.105","DOIUrl":"10.1089/hum.2024.105","url":null,"abstract":"<p><p>The invention of next-generation CRISPR/Cas gene editing tools, like base and prime editing, for correction of gene variants causing disease, has created hope for <i>in vivo</i> use in patients leading to wider clinical translation. To realize this potential, delivery vehicles that can ferry gene editing tool kits safely and effectively into specific cell populations or tissues are in great demand. In this review, we describe the development of enveloped retrovirus-derived particles as carriers of \"ready-to-work\" ribonucleoprotein complexes consisting of Cas9-derived editor proteins and single guide RNAs. We present arguments for adapting viruses for cell-targeted protein delivery and describe the status after a decade-long development period, which has already shown effective editing in primary cells, including T cells and hematopoietic stem cells, and in tissues targeted <i>in vivo</i>, including mouse retina, liver, and brain. Emerging evidence has demonstrated that engineered virus-derived nanoparticles can accommodate both base and prime editors and seems to fertilize a sprouting hope that such particles can be further developed and produced in large scale for therapeutic applications.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"604-616"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SP-101, A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Cystic Fibrosis, Mediates Functional Correction of Primary Human Airway Epithelia From Donors with Cystic Fibrosis.","authors":"Katherine J D A Excoffon, Shen Lin, Poornima Kotha Lakshmi Narayan, Sneha Sitaraman, Awal M Jimah, Tyler T Fallon, Melane L James, Matthew R Glatfelter, Maria P Limberis, Mark D Smith, Guia Guffanti, Roland Kolbeck","doi":"10.1089/hum.2024.063","DOIUrl":"10.1089/hum.2024.063","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human <i>CFTR</i> minigene, <i>hCFTRΔR</i>, and is being investigated as an inhalation treatment for people with CF. To further understand SP-101 activity, <i>in vitro</i> studies were performed in human airway epithelia (HAE) derived from multiple CF and non-CF donors. SP-101 restored CFTR-mediated chloride conductance, measured via Ussing chamber assay, at a multiplicity of infection (MOI) as low as 5E2 in the presence of doxorubicin, a small molecule known to augment AAV transduction. Functional correction of CF HAE increased with increasing MOI and doxorubicin concentration and correlated with increasing cell-associated vector genomes and <i>hCFTRΔR</i> mRNA expression. Tropism studies using a fluorescent reporter vector and single-cell mRNA sequencing of SP-101-mediated <i>hCFTRΔR</i> mRNA demonstrated broad expression in all cell types after apical transduction, including secretory, ciliated, and basal cells. In summary, SP-101, particularly in combination with doxorubicin, shows promise for a novel CF treatment strategy and strongly supports continued development.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"695-709"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}