Gene Therapy最新文献_第7页

Retraction Note: Long noncoding RNA RBMS3-AS3 acts as a microRNA-4534 sponge to inhibit the progression of prostate cancer by upregulating VASH1 撤稿说明：长非编码 RNA RBMS3-AS3 可作为 microRNA-4534 的海绵，通过上调 VASH1 抑制前列腺癌的进展。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-09 DOI: 10.1038/s41434-023-00439-5

Zhenming Jiang, Yuxi Zhang, Xi Chen, Pingeng Wu, Dong Chen

引用次数: 0

Ghrelin mediated cardioprotection using in vitro models of oxidative stress 利用体外氧化应激模型研究胃泌素介导的心脏保护作用

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00435-9

Cindy Y. Kok, George Ghossein, Sindhu Igoor, Renuka Rao, Tracy Titus, Shinya Tsurusaki, James JH. Chong, Eddy Kizana

{"title":"Ghrelin mediated cardioprotection using in vitro models of oxidative stress","authors":"Cindy Y. Kok, George Ghossein, Sindhu Igoor, Renuka Rao, Tracy Titus, Shinya Tsurusaki, James JH. Chong, Eddy Kizana","doi":"10.1038/s41434-023-00435-9","DOIUrl":"10.1038/s41434-023-00435-9","url":null,"abstract":"Ghrelin is commonly known as the ‘hunger hormone’ due to its role in stimulating food intake in humans. However, the roles of ghrelin extend beyond regulating hunger. Our aim was to investigate the ability of ghrelin to protect against hydrogen peroxide (H2O2), a reactive oxygen species commonly associated with cardiac injury. An in vitro model of oxidative stress was developed using H2O2 injured H9c2 cells. Despite lentiviral ghrelin overexpression, H9c2 cell viability and mitochondrial function were not protected following H2O2 injury. We found that H9c2 cells lack expression of the preproghrelin cleavage enzyme prohormone convertase 1 (encoded by PCSK1), required to convert ghrelin to its active form. In contrast, we found that primary rat cardiomyocytes do express PCSK1 and were protected from H2O2 injury by lentiviral ghrelin overexpression. In conclusion, we have shown that ghrelin expression can protect primary rat cardiomyocytes against H2O2, though this effect was not observed in other cell types tested.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00435-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139093662","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

Correction: Cost of gene therapy 更正：基因治疗的成本。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00432-y

Patrick T. Harrison, Theodore Friedmann

引用次数: 0

CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering CRISPR/Cas9 介导的碱基编辑器及其在线粒体基因组工程中的应用前景

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00434-w

Shahin Eghbalsaied, Clancy Lawler, Björn Petersen, Raul A. Hajiyev, Steve R. Bischoff, Stephen Frankenberg

{"title":"CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering","authors":"Shahin Eghbalsaied, Clancy Lawler, Björn Petersen, Raul A. Hajiyev, Steve R. Bischoff, Stephen Frankenberg","doi":"10.1038/s41434-023-00434-w","DOIUrl":"10.1038/s41434-023-00434-w","url":null,"abstract":"Base editors are a type of double-stranded break (DSB)-free gene editing technology that has opened up new possibilities for precise manipulation of mitochondrial DNA (mtDNA). This includes cytosine and adenosine base editors and more recently guanosine base editors. Because of having low off-target and indel rates, there is a growing interest in developing and evolving this research field. Here, we provide a detailed update on DNA base editors. While base editing has widely been used for nuclear genome engineering, the growing interest in applying this technology to mitochondrial DNA has been faced with several challenges. While Cas9 protein has been shown to enter mitochondria, use of smaller Cas proteins, such as Cas12a, has higher import efficiency. However, sgRNA transfer into mitochondria is the most challenging step. sgRNA structure and ratio of Cas protein to sgRNA are both important factors for efficient sgRNA entry into mitochondria. In conclusion, while there are still several challenges to be addressed, ongoing research in this field holds the potential for new treatments and therapies for mitochondrial disorders.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00434-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139093507","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

CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy CSTB基因置换可改善小鼠1型进行性肌阵挛癫痫的神经炎症、神经变性和共济失调。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-12-22 DOI: 10.1038/s41434-023-00433-x

Emrah Gumusgoz, Sahba Kasiri, Mayank Verma, Jun Wu, Daniel Villarreal Acha, Ummay Marriam, Sharyl Fyffe-Maricich, Amy Lin, Xin Chen, Steven J. Gray, Berge A. Minassian

{"title":"CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy","authors":"Emrah Gumusgoz, Sahba Kasiri, Mayank Verma, Jun Wu, Daniel Villarreal Acha, Ummay Marriam, Sharyl Fyffe-Maricich, Amy Lin, Xin Chen, Steven J. Gray, Berge A. Minassian","doi":"10.1038/s41434-023-00433-x","DOIUrl":"10.1038/s41434-023-00433-x","url":null,"abstract":"EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children’s normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138884832","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

Distributional comparison of different AAV vectors after unilateral cochlear administration 单侧耳蜗给药后不同 AAV 向量的分布比较

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-12-14 DOI: 10.1038/s41434-023-00431-z

Shuang Han, Zhijiao Xu, Shengyi Wang, Honghai Tang, Shaowei Hu, Hui Wang, Guofang Guan, Yilai Shu

{"title":"Distributional comparison of different AAV vectors after unilateral cochlear administration","authors":"Shuang Han, Zhijiao Xu, Shengyi Wang, Honghai Tang, Shaowei Hu, Hui Wang, Guofang Guan, Yilai Shu","doi":"10.1038/s41434-023-00431-z","DOIUrl":"10.1038/s41434-023-00431-z","url":null,"abstract":"The adeno-associated virus (AAV) gene therapy has been widely applied to mouse models for deafness. But, AAVs could transduce non-targeted organs after inner ear delivery due to their low cell-type specificity. This study compares transgene expression and biodistribution of AAV1, AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB after round window membrane (RWM) injection in neonatal mice. The highest virus concentration was detected in the injected cochlea. AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB transduced both inner hair cells (IHCs) and outer hair cells (OHCs) with high efficiency, while AAV1 transduced IHCs with high efficiency but OHCs with low efficiency. All AAV subtypes finitely transduced contralateral inner ear, brain, heart, and liver compared with the injected cochlea. In most brain regions, the enhanced green fluorescent protein (eGFP) expression of AAV1 and AAV2 was lower than that of other four subtypes. We suggested the cochlear aqueduct might be one of routes for vectors instantaneously infiltrating into the brain from the cochlea through a dye tracking test. In summary, our results provide available data for further investigating the biodistribution of vectors through local inner ear injection and afford a reference for selecting AAV serotypes for gene therapy toward deafness.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138689412","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

Engineered compact pan-neuronal promoter from Alphaherpesvirus LAP2 enhances target gene expression in the mouse brain and reduces tropism in the liver 来自Alphaherpesvirus LAP2的工程紧凑型泛神经元启动子增强了靶基因在小鼠脑中的表达并减少了在肝脏中的趋向性。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-11-27 DOI: 10.1038/s41434-023-00430-0

Carola J. Maturana

{"title":"Engineered compact pan-neuronal promoter from Alphaherpesvirus LAP2 enhances target gene expression in the mouse brain and reduces tropism in the liver","authors":"Carola J. Maturana","doi":"10.1038/s41434-023-00430-0","DOIUrl":"10.1038/s41434-023-00430-0","url":null,"abstract":"Small promoters capable of driving potent neuron-restricted gene expression are required to support successful brain circuitry and clinical gene therapy studies. However, converting large promoters into functional MiniPromoters, which can be used in vectors with limited capacity, remains challenging. In this study, we describe the generation of a novel version of alphaherpesvirus latency-associated promoter 2 (LAP2), which facilitates precise transgene expression exclusively in the neurons of the mouse brain while minimizing undesired targeting in peripheral tissues. Additionally, we aimed to create a compact neural promoter to facilitate packaging of larger transgenes. Our results revealed that MiniLAP2 (278 bp) drives potent transgene expression in all neurons in the mouse brain, with little to no expression in glial cells. In contrast to the native promoter, MiniLAP2 reduced tropism in the spinal cord and liver. No expression was detected in the kidney or skeletal muscle. In summary, we developed a minimal pan-neuronal promoter that drives specific and robust transgene expression in the mouse brain when delivered intravenously via AAV-PHP.eB vector. The use of this novel MiniPromoter may broaden the range of deliverable therapeutics and improve their safety and efficacy by minimizing the potential for off-target effects.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00430-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444465","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

Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa 展望:非洲镰状细胞病体细胞基因治疗的伦理和社会挑战。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-11-27 DOI: 10.1038/s41434-023-00429-7

Nchangwi Syntia Munung, Obiageli E. Nnodu, Patrick Ohiani Moru, Akpaka A. Kalu, Benido Impouma, Marsha J. Treadwell, Ambroise Wonkam

{"title":"Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa","authors":"Nchangwi Syntia Munung, Obiageli E. Nnodu, Patrick Ohiani Moru, Akpaka A. Kalu, Benido Impouma, Marsha J. Treadwell, Ambroise Wonkam","doi":"10.1038/s41434-023-00429-7","DOIUrl":"10.1038/s41434-023-00429-7","url":null,"abstract":"Somatic gene therapy will be one of the most exciting practices of genetic medicine in Africa and is primed to offer a “new life” for persons living with sickle cell disease (SCD). Recently, successful gene therapy trials for SCD in the USA have sparked a ray of hope within the SCD community in Africa. However, the high cost, estimated to exceed 1.5 million USD, continues to be a major concern for many stakeholders. While affordability is a key global health equity consideration, it is equally important to reflect on other ethical, legal and social issues (ELSIs) that may impact the responsible implementation of gene therapy for SCD in Africa. These include informed consent comprehension, risk of therapeutic misestimation and optimistic bias; priorities for SCD therapy trials; dearth of ethical and regulatory oversight for gene therapy in many African countries; identifying a favourable risk-benefit ratio; criteria for the selection of trial participants; decisional conflict in consent; standards of care; bounded justice; and genetic tourism. Given these ELSIs, we suggest that researchers, pharma, funders, global health agencies, ethics committees, science councils and SCD patient support/advocacy groups should work together to co-develop: (1) patient-centric governance for gene therapy in Africa, (2) public engagement and education materials, and (3) decision making toolkits for trial participants. It is also critical to establish harmonised ethical and regulatory frameworks for gene therapy in Africa, and for global health agencies to accelerate access to basic care for SCD in Africa, while simultaneously strengthening capacity for gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00429-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444393","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

Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement 人类神经母细胞瘤细胞戊二酸尿I型模型再现了可通过基因替代拯救的神经元损伤。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-11-20 DOI: 10.1038/s41434-023-00428-8

A. Mateu-Bosch, E. Segur-Bailach, J. García-Villoria, S. Gea-Sorlí, I. Ruiz, J. del Rey, J. Camps, M. Guitart-Mampel, G. Garrabou, F. Tort, A. Ribes, C. Fillat

{"title":"Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement","authors":"A. Mateu-Bosch, E. Segur-Bailach, J. García-Villoria, S. Gea-Sorlí, I. Ruiz, J. del Rey, J. Camps, M. Guitart-Mampel, G. Garrabou, F. Tort, A. Ribes, C. Fillat","doi":"10.1038/s41434-023-00428-8","DOIUrl":"10.1038/s41434-023-00428-8","url":null,"abstract":"Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176074","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

Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability 主神经元中KCNN4通道的过表达在不降低其编码能力的情况下产生抗癫痫作用。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-11-15 DOI: 10.1038/s41434-023-00427-9

Evgeny S. Nikitin, Tatiana Y. Postnikova, Elena Y. Proskurina, Anastasia A. Borodinova, Violetta Ivanova, Matvey V. Roshchin, Maria P. Smirnova, Ilya Kelmanson, Vsevolod V. Belousov, Pavel M. Balaban, Aleksey V. Zaitsev

{"title":"Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability","authors":"Evgeny S. Nikitin, Tatiana Y. Postnikova, Elena Y. Proskurina, Anastasia A. Borodinova, Violetta Ivanova, Matvey V. Roshchin, Maria P. Smirnova, Ilya Kelmanson, Vsevolod V. Belousov, Pavel M. Balaban, Aleksey V. Zaitsev","doi":"10.1038/s41434-023-00427-9","DOIUrl":"10.1038/s41434-023-00427-9","url":null,"abstract":"Gene therapy offers a potential alternative to the surgical treatment of epilepsy, which affects millions of people and is pharmacoresistant in ~30% of cases. Aimed at reducing the excitability of principal neurons, the engineered expression of K+ channels has been proposed as a treatment due to the outstanding ability of K+ channels to hyperpolarize neurons. However, the effects of K+ channel overexpression on cell physiology remain to be investigated. Here we report an adeno-associated virus (AAV) vector designed to reduce epileptiform activity specifically in excitatory pyramidal neurons by expressing the human Ca2+-gated K+ channel KCNN4 (KCa3.1). Electrophysiological and pharmacological experiments in acute brain slices showed that KCNN4-transduced cells exhibited a Ca2+-dependent slow afterhyperpolarization that significantly decreased the ability of KCNN4-positive neurons to generate high-frequency spike trains without affecting their lower-frequency coding ability and action potential shapes. Antiepileptic activity tests showed potent suppression of pharmacologically induced seizures in vitro at both single cell and local field potential levels with decreased spiking during ictal discharges. Taken together, our findings strongly suggest that the AAV-based expression of the KCNN4 channel in excitatory neurons is a promising therapeutic intervention as gene therapy for epilepsy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134648784","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