Gene Therapy最新文献_第4页

A capless hairpin-protected mRNA vaccine encoding the full-length Influenza A hemagglutinin protects mice against a lethal Influenza A infection. 一种编码全长甲型流感血凝素的无帽发夹保护mRNA疫苗保护小鼠免受致命甲型流感感染。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-23 DOI: 10.1038/s41434-025-00521-0

Victor Solodushko, Jin H Kim, Brian Fouty

{"title":"A capless hairpin-protected mRNA vaccine encoding the full-length Influenza A hemagglutinin protects mice against a lethal Influenza A infection.","authors":"Victor Solodushko, Jin H Kim, Brian Fouty","doi":"10.1038/s41434-025-00521-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00521-0","url":null,"abstract":"The success of mRNA vaccines in controlling the COVID 19 pandemic has confirmed the efficacy of synthetically synthesized mRNA in humans and has also provided a blueprint on how to design them in terms of molecular structure and cost. We describe a mRNA vector that, unlike linear mRNAs used in current vaccines/therapeutics, does not require a 5' cap to function. The described mRNA vector initiates translation from an internal ribosomal entry site (IRES) and contains specially designed self-folding secondary structures (hairpins) to protect the 5' end against degradation, dramatically improving its stability. The produced mRNA did not require any additional modifications for functionality. The 5' hairpins completely inhibited cap-dependent translation, and all vectors containing them required an IRES to express protein. When this capless mRNA vector was constructed to express the full-length Influenza A membrane protein hemagglutinin (HA), complexed with pre-formed lipid-based nanoparticles, and then injected into mice as a vaccine, it generated high titers of anti-HA antibodies and protected mice against a lethal dose of Influenza A.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482964","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}

引用次数: 0

AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis. AAV1。NT3基因治疗减轻多发性硬化症小鼠模型自身免疫性脑脊髓炎的严重程度。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-19 DOI: 10.1038/s41434-025-00518-9

Lingying Tong, Burcak Ozes, Kyle Moss, Morgan Myers, Zayed Attia, Tatyana A Vetter, Bruce D Trapp, Zarife Sahenk

{"title":"AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis.","authors":"Lingying Tong, Burcak Ozes, Kyle Moss, Morgan Myers, Zayed Attia, Tatyana A Vetter, Bruce D Trapp, Zarife Sahenk","doi":"10.1038/s41434-025-00518-9","DOIUrl":"https://doi.org/10.1038/s41434-025-00518-9","url":null,"abstract":"Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than 2.5 million patients worldwide. Chronic demyelination in the CNS has an important role in perpetuating axonal loss and increases difficulty in promoting remyelination. Therefore, regenerative, and neuroprotective strategies are essential to overcome this impediment to rescue axonal integrity and function. Neurotrophin 3 (NT-3) has immunomodulatory and anti-inflammatory properties, in addition to its well-recognized function in nervous system development, myelination, neuroprotection, and regeneration. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of experimental autoimmune encephalomyelitis (EAE) mice, the chronic relapsing mouse model of MS, at 3 weeks post EAE induction. Measurable NT-3 levels were found in serum at 7-weeks post gene delivery. The treated cohort showed improved clinical scores and performed significantly better in rotarod, and grip strength tests compared to their untreated counterparts. Histopathologic studies showed improved remyelination and axon protection. These data correlated with reduced expression of the pro-inflammatory cytokines in brain and spinal cord, and increased percentage of regulatory T cells in the spleens and lymph nodes. Collectively, these findings demonstrate the translational potential of AAV-delivered NT-3 for chronic progressive MS.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457602","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}

引用次数: 0

A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice 一种肽偶联物可以使morpholino诱导剂全身注射，并在小鼠中更持久地诱导T3H38核酶控制的AAV转基因。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-12 DOI: 10.1038/s41434-025-00519-8

Xiaojuan Tang, Haimin Wang, Yandong Yin, Guocai Zhong

{"title":"A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice","authors":"Xiaojuan Tang, Haimin Wang, Yandong Yin, Guocai Zhong","doi":"10.1038/s41434-025-00519-8","DOIUrl":"10.1038/s41434-025-00519-8","url":null,"abstract":"Genetic switches that allow for precise control over transgene expression timing or levels may improve the safety and expand the use of adeno-associated viral (AAV) vector-based gene therapy technologies. We previously engineered an efficient RNA switch system that comprises a novel self-cleaving ribozyme (T3H38) and an octaguanidine dendrimer-conjugated morpholino oligonucleotide (v-M8) complementary to the ribozyme. This switch system can be used to efficiently regulate AAV-delivered transgenes with an up to 200-fold regulatory range in mice. However, this switch system has a relatively short induction half-life and only works well when v-M8 was locally but not systemically administered, representing two key limitations of the system. To address these issues, here, we tested replacing the octa-guanidine dendrimer in the v-M8 morpholino oligo with a cell-penetrating peptide (CPP). Two CPP-conjugated morpholino oligos (B-M8 and B-MSP-M8) were synthesized and compared with v-M8 for the induction of T3H38-regulated AAV-luciferase in mice. One of the CPP-conjugated oligos (B-MSP-M8) not only showed significantly improved induction half-life over that of v-M8, but also enabled efficient induction of AAV transgene expression when the oligo was systemically administered. This study improves in vivo performance and broadens the utility of the T3H38 ribozyme-based RNA switch system in gene therapy applications.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"163-171"},"PeriodicalIF":4.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407108","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}

引用次数: 0

Correction: The disparate burden of infectious diseases 更正：传染病造成的不同负担。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-26 DOI: 10.1038/s41434-025-00516-x

Kristie Bloom

引用次数: 0

Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy. 基因治疗后靶向蛋白质组学发现脊髓性肌萎缩症的新反应标志物。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-10 DOI: 10.1038/s41434-025-00513-0

Devesh C Pant, Sumit Verma

{"title":"Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy.","authors":"Devesh C Pant, Sumit Verma","doi":"10.1038/s41434-025-00513-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00513-0","url":null,"abstract":"Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964493","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}

引用次数: 0

AAV library screening identifies novel vector for efficient transduction of human aorta AAV文库筛选为人类主动脉高效转导找到了新的载体。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-18 DOI: 10.1038/s41434-024-00511-8

Lena C. Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C. Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J. Müller

{"title":"AAV library screening identifies novel vector for efficient transduction of human aorta","authors":"Lena C. Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C. Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J. Müller","doi":"10.1038/s41434-024-00511-8","DOIUrl":"10.1038/s41434-024-00511-8","url":null,"abstract":"Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding. This approach allowed us to distinguish capsids that only transduce cells based on genomic DNA (gDNA) from those also mediating transgene expression based on transcribed cDNA reads. After three rounds of selection on primary murine VSMCs (mVSMCs), we identified a novel targeting motif (RFTEKPA) that significantly improved transduction and gene expression efficiency over AAV9-wild type (WT) and increased expression in mVSMCs by 70% compared to the previously identified SLRSPPS peptide. Further analysis showed that the novel motif also improved expression in human aortic smooth muscle cells (HAoSMCs) and human aortic tissue ex vivo up to threefold compared to SLRSPPS and approximately 70-fold to AAV9-WT. This high cross-species transduction efficiency makes the novel capsid motif a potential candidate for future clinical application in vascular diseases.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"154-162"},"PeriodicalIF":4.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00511-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853989","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}

引用次数: 0

Unlocking patient access to gene therapy: five key practices 开启患者获得基因治疗的途径：五个关键实践。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-06 DOI: 10.1038/s41434-024-00509-2

Tay Salimullah, Burcu Kazazoglu Taylor, Madeleine Zerbato

引用次数: 0

Adeno-associated virus serotype 2 capsids with proteolytic cuts by trypsin remain intact and potent 腺相关病毒血清2型衣壳被胰蛋白酶蛋白水解切割后保持完整和有效。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-29 DOI: 10.1038/s41434-024-00507-4

Yu Zhou, Tina Sach, Joseph Y. Ong, Ting-An Lim, Zoltan Berecz, Colin Deniston, Goran Milicic, Connie Y. Tsai, Taryn Kandepalli, Derek J. Langeslay, Qiang Qin

{"title":"Adeno-associated virus serotype 2 capsids with proteolytic cuts by trypsin remain intact and potent","authors":"Yu Zhou, Tina Sach, Joseph Y. Ong, Ting-An Lim, Zoltan Berecz, Colin Deniston, Goran Milicic, Connie Y. Tsai, Taryn Kandepalli, Derek J. Langeslay, Qiang Qin","doi":"10.1038/s41434-024-00507-4","DOIUrl":"10.1038/s41434-024-00507-4","url":null,"abstract":"Recombinant adeno-associated viral (AAV) vectors have emerged as prominent gene delivery vehicles for gene therapy. In the journey of an AAV vector, AAV vectors can be exposed to different proteolytic environments inside the production cells, during the cell lysis step, within the endosome, and finally inside the cell nucleus. The stability of a modified AAV serotype 2 (AAV2) capsid was evaluated via a proteolytic approach using trypsin and other proteases and both denaturing and non-denaturing analytical methods. Trypsin digestion of the AAV2 capsids resulted in clips of the capsid proteins at the C-terminus as confirmed by denaturing methods including SDS-PAGE, CE-SDS, Western blot, and RPLC-MS. It was found that the AAV2 capsid with clips not only remains structurally intact, as confirmed by non-denaturing methods including SEC, thermostability testing, and cryo-EM, but also remains potent, as confirmed in a cell-based potency assay. This finding reveals that AAV2 capsid with proteolytic cuts remains intact and potent since the icosahedral three-dimensional structural arrangement of AAV capsid proteins can protect the clipped fragment from being released from the capsid, such that the AAV capsid remains intact allowing for the functionality to be maintained to deliver the DNA in the host cell. Evaluation of AAV stability using a proteolytic approach and multiple denaturing and non-denaturing analytical methods can provide valuable information for engineering AAV capsids to develop AAV-based gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"121-131"},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00507-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754970","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}

引用次数: 0

Prime editing: therapeutic advances and mechanistic insights 主要编辑：治疗进展和机制见解。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-28 DOI: 10.1038/s41434-024-00499-1

Joss B. Murray, Patrick T. Harrison, Janine Scholefield

{"title":"Prime editing: therapeutic advances and mechanistic insights","authors":"Joss B. Murray, Patrick T. Harrison, Janine Scholefield","doi":"10.1038/s41434-024-00499-1","DOIUrl":"10.1038/s41434-024-00499-1","url":null,"abstract":"We are often confronted with a simple question, “which gene editing technique is the best?”; the simple answer is “there isn’t one”. In 2021, a year after prime editing first made its mark, we evaluated the landscape of this potentially transformative advance in genome engineering towards getting treatments to the clinic [1]. Nearly 20% of the papers we cited were still in pre-print at the time which serves to indicate how early-stage the knowledge base was at that time. Now, three years later, we take a look at the landscape and ask what has been learnt to ensure this tech is broadly accessible, highlighting some key advances, especially those that push this towards the clinic. A big part of the appeal of prime editing is its ability to precisely edit DNA without double stranded breaks, and to install any of the 12 possible single-nucleotide conversion events as well as small insertions and/or deletions, or essentially any combination thereof. Over the last few decades, other transformative and Nobel prize-winning technologies that rely on Watson-Crick base-pairing such as PCR, site-directed mutagenesis, RNA interference, and one might say, “classic” CRISPR, were swiftly adopted across labs around the world because of the speed with which mechanistic rules governing their efficiency were determined. Whilst this perspective focuses on the context of gene therapy applications of prime editing, we also further look at the recent studies which have increased our understanding of the mechanism of PEs and simultaneously improved the efficiency and diversity of the PE toolbox.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"83-92"},"PeriodicalIF":4.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00499-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750784","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}

引用次数: 0

Gene-based therapy for the treatment of spinal muscular atrophy types 1 and 2 : a systematic review and meta-analysis. 治疗脊髓性肌萎缩症 1 型和 2 型的基因疗法：系统综述和荟萃分析。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-27 DOI: 10.1038/s41434-024-00503-8

Bunchai Chongmelaxme, Varalee Yodsurang, Ponlawat Vichayachaipat, Thanate Srimatimanon, Oranee Sanmaneechai

{"title":"Gene-based therapy for the treatment of spinal muscular atrophy types 1 and 2 : a systematic review and meta-analysis.","authors":"Bunchai Chongmelaxme, Varalee Yodsurang, Ponlawat Vichayachaipat, Thanate Srimatimanon, Oranee Sanmaneechai","doi":"10.1038/s41434-024-00503-8","DOIUrl":"https://doi.org/10.1038/s41434-024-00503-8","url":null,"abstract":"Despite numerous studies identifying the advantages of therapies for spinal muscular atrophy (SMA), healthcare professionals encounter obstacles in determining the most effective treatment. This study aimed to investigate the effects of gene-based therapy for SMA. A systematic search was conducted from inception to May 2024 across databases, and all studies assessing the effects of gene-based therapy on patients with SMA types 1 and 2 were included. The outcomes measured were survival, the need for ventilatory support, improvements in motor function, and the occurrence of adverse drug reactions. Meta-analyses were performed using a random-effects model. A total of 57 studies (n = 3418) were included, and the meta-analyses revealed that onasemnogene abeparvovec showed the highest survival rate (95% [95% CI: 88, 100]), followed by risdiplam (86% [95% CI: 76, 94]) and nusinersen (60% [95% CI: 50, 70]). The number of patients needing ventilatory support was reduced after treatment with onasemnogene abeparvovec (risk ratio = 0·10 [95% CI: 0·02, 0·53]). Onasemnogene abeparvovec and risdiplam had similar proportions of patients with improvements in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score of ≥4 points (92% [95% CI: 62, 100] vs 90% [95% CI: 77, 97]). In contrast, nusinersen had the smallest improvement (74% [95% CI: 66, 81]). The most frequently observed adverse drug reactions were headaches, vomiting, and gastrointestinal disorders. Gene-based therapy benefits patient survival and improves motor function. Onasemnogene abeparvovec and risdiplam appear highly effective, whereas nusinersen exhibits moderate effectiveness.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739263","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}

引用次数: 0