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

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

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

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

Gene therapy

Gene Ther

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

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

Spinal muscular atrophy (SMA) is a genetically inherited recessive neuromuscular disease that causes muscular atrophy and weakness. Onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) is a targeted therapy approved to treat patients with SMA in >40 countries worldwide. This study describes the clinical efficacy and tolerability of gene replacement therapy with onasemnogene abeparvovec over a 3-month period in 9 SMA type 1 patients aged 1.7-48 months, with 7 patients on stable nusinersen (i.e., had received all four nusinersen loading doses before inclusion in this study). Liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin), troponin I, platelet counts, creatinine levels, and motor function (CHOP-INTEND) were monitored. For the seven patients on stable nusinersen, the median baseline CHOP-INTEND score increased significantly during nusinersen treatment (Wilcoxon signed-rank test p = 0.018) and at 3 months after switching to onasemnogene abeparvovec (Wilcoxon signed-rank test p = 0.0467). We also identified two patients who responded poorly to nusinersen but showed the largest increase in baseline CHOP-INTEND scores at 1 and 3 months after switching, which could suggest that poor responders to nusinersen may respond favorably to onasemnogene abeparvovec. No unknown adverse events occurred. One patient developed moderate/severe thrombocytopenia 1 week after onasemnogene abeparvovec administration that resolved after treatment. Our study suggests the possibility of a change in the dynamic of CHOP-INTEND for patients who respond poorly to nusinersen after switching therapy to onasemnogene abeparvovec. Alternatively, patient age at treatment initiation may impact the response to onasemnogene abeparvovec. Testing in larger patient populations must be undertaken to assess the plausibility of these hypotheses.

Ilaria Bitetti

Valentina Lanzara

Giovanna Margiotta

Antonio Varone

Onasemnogene abeparvovec gene replacement therapy for the treatment of spinal muscular atrophy: a real-world observational study

脊髓性肌萎缩症的Onasemnogene abeparvovec基因替代疗法：真实世界的观察性研究

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

Adeno-associated virus serotype 2 capsids with proteolytic cuts by trypsin remain intact and potent

胰蛋白酶切割的腺相关病毒2型衣壳保持完整且具有活性

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.

Joss B. Murray

Patrick T. Harrison

Janine Scholefield

Prime editing: therapeutic advances and mechanistic insights

精准编辑：治疗进展与机制洞察

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.

Bunchai Chongmelaxme

Varalee Yodsurang

Ponlawat Vichayachaipat

Thanate Srimatimanon

Oranee Sanmaneechai

Gene-based therapy for the treatment of spinal muscular atrophy types 1 and 2 : a systematic review and meta-analysis

基于基因治疗的脊髓性肌萎缩症1型和2型治疗：系统综述与Meta分析

Abstract Low back pain is the leading cause of global disability with intervertebral disc (IVD) degeneration a major cause. However, no current treatments target the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist, the signalling inhibitor of the pro-inflammatory cytokine interleukin-1, which orchestrates the catabolic degeneration of the IVD. Here, the ability of PCRX-201 to transduce human nucleus pulposus cells to increase IL-1Ra production was assessed together with effects on catabolic pathways. When transduced with PCRX-201, the production and release of IL-1Ra was increased in degenerate human nucleus pulposus cells and tissue. Whereas, the production of downstream proteins, including IL-1β, IL-6, MMP3, ADAMTS4 and VEGF were decreased in both cells and tissue, indicating a reduction in IL-1-induced catabolic signalling. Here, a novel gene therapy vector, PCRX-201, was shown to transduce degenerate NP cells and tissue, increasing the production of IL-1Ra. The increased IL-1Ra resulted in decreased production of catabolic cytokines, enzymes and angiogenic factors, whilst also increasing aggrecan expression. This demonstrates PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. The ability of PCRX-201 to elicit anti-catabolic responses is promising and warrants further development to determine the efficacy of this exciting, novel gene therapy.

Joseph W. Snuggs

Rebecca K. Senter

Joshua P. Whitt

J. Derek Jackson

Christine L. Le Maitre

PCRX-201, a novel IL-1Ra gene therapy treatment approach for low back pain resulting from intervertebral disc degeneration

PCRX-201，一种针对椎间盘退变所致下腰痛的新型IL-1Ra基因治疗方案

Christopher H. Evans

Genes for bad backs

坏背基因

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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