基因疗法涵盖了基于遗传成分的新型治疗技术的研究和临床应用。在过去的几十年里，从识别导致疾病的新遗传靶点到显示治疗益处的临床研究，技术的重大进步已将这一多学科领域提升到现代医学的前沿。

Gene Therapy is a field that focuses on the research and clinical application of novel therapeutic techniques based on genetic components. In recent decades, significant advancements in technology have elevated this multidisciplinary field to the forefront of modern medicine, from identifying new genetic targets that cause diseases to demonstrating therapeutic benefits in clinical studies.

基因疗法是研究和临床应用基于遗传成分的新型治疗技术的领域。近年来，随着对导致疾病的新遗传靶点的识别以及临床研究中治疗效果的展示，这一多学科领域的技术进步显著，已将其提升至现代医学的前沿。

Gene Therapy

T R Flotte

Gene therapy

Gene Ther

Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV) vectors.

基因治疗进展与展望：重组腺相关病毒（rAAV）载体。

Decitabine, which reverses hypermethylation of the p15INK4B gene in vitro, has been used to relieve cytopenias and blast excess in over 50% of patients with high-risk myelodysplastic syndrome (MDS). In this study, heme oxygenase-1 (HO-1) was overexpressed in MDS cell line SKM-1, which was closely related to resistance to decitabine-induced apoptosis. We aimed to further investigate the role of HO-1 in apoptosis induced by low-dose decitabine in SKM-1 cells. Upregulation of HO-1 by transfecting it into SKM-1 cells with lentivirus vector promoted cell proliferation and protected them against apoptosis. In contrast, downregulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of the S phase in cell cycle. To explore the mechanism, the expressions of cell cycle-related proteins were detected after the cells were treated by decitabine in each group. p15INK4B and CDK4 were overexpressed in SKM-1 cells in which HO-1 was inhibited, and the expression-depending apoptosis was related to the caspase-3 pathway. Even though HO-1 was silenced, the apoptotic rate never increased as the caspase-3 pathway was blocked. It is well known that p15INK4B dominantly regulates the S phase of the cell cycle. p15INK4B was herein demethylated more evidently in the group of SKM-1 cells in which HO-1 was downregulated, as well as in the mononuclear cells of patients suffering from MDS. In the case of poor prognosis, the mRNA level of HO-1 was raised. In conclusion, overexpression of HO-1 indicated resistance to demethylation of p15INK4B induced by decitabine.

D Ma

Q Fang

P Wang

R Gao

J Sun

Y Li

X Y Hu

J S Wang

Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome

HO-1下调通过增加p15INK4B启动子去甲基化促进地西他滨诱导的骨髓增生异常综合征细胞凋亡

We have demonstrated the potential of random peptide libraries displayed on adeno-associated virus (AAV)2 to select for AAV2 vectors with improved efficiency for cell type-directed gene transfer. AAV9, however, may have advantages over AAV2 because of a lower prevalence of neutralizing antibodies in humans and more efficient gene transfer in vivo. Here we provide evidence that random peptide libraries can be displayed on AAV9 and can be utilized to select for AAV9 capsids redirected to the cell type of interest. We generated an AAV9 peptide display library, which ensures that the displayed peptides correspond to the packaged genomes and performed four consecutive selection rounds on human coronary artery endothelial cells in vitro. This screening yielded AAV9 library capsids with distinct peptide motifs enabling up to 40-fold improved transduction efficiencies compared with wild-type (wt) AAV9 vectors. Incorporating sequences selected from AAV9 libraries into AAV2 capsids could not increase transduction as efficiently as in the AAV9 context. To analyze the potential on endothelial cells in the intact natural vascular context, human umbilical veins were incubated with the selected AAV in situ and endothelial cells were isolated. Fluorescence-activated cell sorting analysis revealed a 200-fold improved transduction efficiency compared with wt AAV9 vectors. Furthermore, AAV9 vectors with targeting sequences selected from AAV9 libraries revealed an increased transduction efficiency in the presence of human intravenous immunoglobulins, suggesting a reduced immunogenicity. We conclude that our novel AAV9 peptide library is functional and can be used to select for vectors for future preclinical and clinical gene transfer applications.

K Varadi

S Michelfelder

T Korff

M Hecker

M Trepel

H A Katus

J A Kleinschmidt

O J Müller

Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors

用于筛选内皮细胞定向基因转移载体的新型随机肽库在AAV血清型9上的展示

Development of methods that allow an efficient expression of exogenous genes in animals would provide tools for gene function studies, treatment of diseases and for obtaining gene products. Therefore, we have developed a hydrodynamics-based procedure for expressing transgenes in mice by systemic administration of plasmid DNA. Using cDNA of luciferase and beta-galactosidase as a reporter gene, we demonstrated that an efficient gene transfer and expression can be achieved by a rapid injection of a large volume of DNA solution into animals via the tail vein. Among the organs expressing the transgene, the liver showed the highest level of gene expression. As high as 45 microg of luciferase protein per gram of liver can be achi- eved by a single tail vein injection of 5 microg of plasmid DNA into a mouse. Histochemical analysis using beta-galactosidase gene as a reporter reveals that approximately 40percent of hepatocytes express the transgene. The time-response curve shows that the level of transgene expression in the liver reaches the peak level in approximately 8 h after injection and decreases thereafter. The peak level of gene expression can be regained by repeated injection of plasmid DNA. These results suggest that a simple, convenient and efficient method has been developed and which can be used as an effective means for studying gene function, gene regulation and molecular pathophysiology through gene transfer, as well as for expressing proteins in animals.

F Liu

Y Song

D Liu

Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA.

基于水动力学的动物体内转染：通过系统性注射质粒DNA实现。

Abstract Human gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.

Deepa H. Chand

Rui Sun

Karim A. Diab

Damien Kenny

Francis Fonyuy Tukov

Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings

onaasemnogene abeparvovec基因替代疗法中心脏安全性的回顾：从临床前到临床发现的转化

Lucie Bouquet

Elodie Bôle-Richard

Walid Warda

Mathieu Neto Da Rocha

Rim Trad

Clémentine Nicod

Rafik Haderbache

Delphine Genin

Christophe Ferrand

Marina Deschamps

Correction: RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells

更正：基于RapaCaspase-9的自杀基因应用于IL-1RAP CAR-T细胞的安全性

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.

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

AAV library screening identifies novel vector for efficient transduction of human aorta

AAV文库筛选鉴定出新型载体用于高效转导人类主动脉

Widespread distribution of transduced brain cells following delivery of AAV vectors into the cerebrospinal fluid (CSF) of the cisterna magna (CM) has been demonstrated in large animal brains. In humans, intraventricular injection is preferred to intracisternal injection for CSF delivery due to the risk of brain stem injury. One study in the dog reported adverse reactions to AAV vectors expressing GFP injected into the lateral ventricle but not when injected into the CM. In contrast, AAV expressing mammalian genes in diseased animals have not triggered adverse responses since many genetic diseases also have compromised immune systems. Differences in circulation of CSF from each site could potentially affect vector spread within the brain, but a direct comparison has not been made using both a mammalian gene and immunologically normal animals. In this study we evaluated the dopamine-2-receptor (D2R) variant D2R80A, which is inactivated for intracellular signaling and has been used as a reporter gene in large animal brains. No adverse reactions to the D2R80A gene were observed from either injection route in normal dogs and both routes resulted in comparable distribution of D2R80A within the brain.

Jacqueline E. Hunter

Charles H. Vite

Caitlyn M. Molony

Patricia A. O’Donnell

John H. Wolfe

Intracisternal vs intraventricular injection of AAV1 result in comparable, widespread transduction of the dog brain

AAV1 的脑室内注射与脑室内注射在犬脑中产生相当且广泛的转导效果

Tay Salimullah

Burcu Kazazoglu Taylor

Madeleine Zerbato

Unlocking patient access to gene therapy: five key practices

解锁患者基因治疗通道：五大关键实践

Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.

Baylea N. Davenport

Rebecca L. Wilson

Alyssa A. Williams

Helen N. Jones

Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model

胎盘纳米颗粒介导的IGF1基因治疗在豚鼠模型中纠正胎儿生长受限

Abbreviation	Gene Ther
Journal Impact	4.53
Quartiles(Global)	MEDICINE, RESEARCH & EXPERIMENTAL(Q2)

ISSN	0969-7128, 1476-5462
h-index	174

Publication Information	Publisher: Springer Nature，Publishing cycle: Semimonthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1994，Proportion of original research papers: 91.55%，Self Citation Rate:4.30%， Gold OA Rate: 43.01%
Average review cycle	网友分享经验：偏慢,4-8周
Average recruitment ratio	网友分享经验：较难

Gene Therapy

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