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A Paradox of the Field's Own Success: Unintended Challenges in Bringing Cutting-Edge Science from the Bench to the Market. 领域自身成功的悖论:将尖端科学从实验室推向市场的意外挑战。
IF 4.2 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-02-01 DOI: 10.1089/hum.2023.29264.nyi
Nathan Yingling, Miguel Sena-Esteves, Heather L Gray-Edwards
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引用次数: 0
Danaher Partners with Innovative Genomics Institute, Doudna, and Urnov on Beacon for CRISPR Cures. 丹纳赫与创新基因组研究所、Doudna 和 Urnov 在 CRISPR 治疗灯塔上开展合作。
IF 4.2 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-02-01 DOI: 10.1089/hum.2024.29265.bfs
Alex Philippidis
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引用次数: 0
Adeno-Associated Virus Type 9-Mediated Gene Therapy of Choline Acetyltransferase-Deficient Mice. aav9 介导的胆碱乙酰转移酶缺陷小鼠基因疗法。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-02-01 DOI: 10.1089/hum.2023.173
Cameron V Lin, Clementine A D Thomas, Thanh L Huynh, David T Wei, Jaime N Young, Anahid S Aivazian, Abigail McInnes, Jixiang Xu, Sarah E Cook, Jessica Vazquez, Ricardo A Maselli

The enzyme choline acetyltransferase (ChAT) synthesizes acetylcholine from acetyl-CoA and choline at the neuromuscular junction and at the nerve terminals of cholinergic neurons. Mutations in the ChAT gene (CHAT) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for Chat (Chat-/-) die at birth. To circumvent the lethality of this model, we crossed mutant mice possessing loxP sites flanking Chat exons 4 and 5 with mice that expressed Cre-ERT2. Injection of tamoxifen (Tx) at postnatal (P) day 11 in these mice induced downregulation of Chat, autonomic failure, weakness, and death. However, a proportion of Chatflox/flox-Cre-ERT2 mice receiving at birth an intracerebroventricular injection of 2 × 1013 vg/kg adeno-associated virus type 9 (AAV9) carrying human CHAT (AAV9-CHAT) survived a subsequent Tx injection and lived to adulthood without showing signs of weakness. Likewise, injection of AA9-CHAT by intracisternal injection at P28 after the onset of weakness also resulted in survival to adulthood. The expression of Chat in spinal motor neurons of Chatflox/flox-Cre-ERT2 mice injected with Tx was markedly reduced, but AAV-injected mice showed a robust recovery of ChAT expression, which was mainly translated by the human CHAT RNA. The biodistribution of the viral genome was widespread but maximal in the spinal cord and brain of AAV-injected mice. No significant histopathological changes were observed in the brain, liver, and heart of AAV-injected mice after 1 year follow-up. Thus, AAV9-mediated gene therapy may provide an effective and safe treatment for patients severely affected with CHAT-CMS.

胆碱乙酰转移酶(ChAT)在神经肌肉接头处和胆碱能神经元的神经末梢将乙酰-CoA 和胆碱合成乙酰胆碱。ChAT 基因(CHAT)突变会导致突触前先天性肌无力综合征(CMS),该综合征往往伴有危及生命的呼吸暂停发作。Chat 基因敲除小鼠(Chat -/-)一出生就会死亡。为了避免这种模型的致死性,我们将拥有 Chat 第 4 和第 5 外显子侧翼 loxP 位点的突变小鼠与表达 Cre-ERT2 的小鼠杂交。在这些小鼠出生后第 11 天注射他莫昔芬(Tx)会导致 Chat 下调、自主神经衰竭、虚弱和死亡。然而,在出生时接受脑室内注射 2x1013 vg/kg 携带人类 CHAT 的 9 型腺相关病毒(AAV9)(AAV9-CHAT)的 Chatflox/flox-Cre-ERT2 小鼠中,有一部分在随后的他莫昔芬注射中存活下来,并活到成年,没有出现虚弱症状。同样,在出现乏力症状后的 P28 小鼠体内注射 AAV9-CHAT 也能存活到成年。注射了Tx的Chatflox/flox-Cre-ERT2小鼠脊髓运动神经元中Chat的表达明显减少,但注射了AAV的小鼠显示出ChAT表达的强劲恢复,ChAT主要由人类CHATRNA翻译。病毒基因组的生物分布非常广泛,但在 AAV 注射小鼠的脊髓和大脑中分布最广。随访一年后,AAV 注射小鼠的大脑、肝脏和心脏未发现明显的组织病理学变化。因此,AAV9介导的基因疗法可为严重罹患CHAT-CMS的患者提供有效而安全的治疗。
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引用次数: 0
Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis. 基于腺相关病毒的血友病临床基因疗法的有效性和安全性:系统回顾与荟萃分析。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-02-06 DOI: 10.1089/hum.2023.208
Zeyu Han, Xianyanling Yi, Jin Li, Dazhou Liao, Guangping Gao, Jianzhong Ai

Clinical trials of adeno-associated virus (AAV)-based gene therapy have made remarkable progress in recent years. We aimed to perform a systematic review and meta-analysis of the literature to assess the efficacy and safety of AAV-based gene therapy for hemophilia. We systematically searched the Web of Science, Embase, PubMed, and the Cochrane Database of Systematic Reviews databases, for clinical trials involving patients diagnosed with hemophilia and treated with AAV-mediated gene therapy. Data on the annualized bleeding rate (ABR), annualized infusion rate (AIR), the incidence of treatment-related adverse events (TRAEs), severe adverse events (SAEs), and alanine aminotransferase (ALT) elevation were extracted as our outcomes. A total of 12 articles from 11 clinical trials were selected from 868 articles for meta-analysis. Pooled analyses showed that AAV-based gene therapy in hemophilia patients reduced the number of bleeding events and the number of factor infusion events by an approximate average of 7 per year and 103 per year, respectively. Eighty percent, 18%, and 63% of hemophilia patients had elevated TRAE, SAE, and ALT levels, respectively. Moreover, subgroup analysis found a significant reduction in ABR and AIR 2-3 years after the therapy. Additional findings that were not pooled including coagulation factor activity are presented in the accompanying tables. Our analysis supported the efficacy and safety of AAV-mediated gene therapy for hemophilia, providing evidence for its application as a therapeutic option for widespread clinical use in hemophilia patients in the future.

近年来,基于腺相关病毒(AAV)的基因疗法临床试验取得了显著进展。我们旨在对文献进行系统回顾和荟萃分析,以评估基于 AAV 的血友病基因疗法的有效性和安全性。我们在 Web of Science、Embase、PubMed 和 Cochrane 系统综述数据库中系统地检索了涉及确诊为血友病并接受 AAV 介导的基因治疗的患者的临床试验。我们提取了年出血率(ABR)、年输液率(AIR)以及治疗相关不良事件(TRAE)、严重不良事件(SAE)和丙氨酸氨基转移酶(ALT)升高的发生率等数据作为研究结果。从 868 篇文章中筛选出 11 项临床试验中的 12 篇文章进行荟萃分析。汇总分析表明,基于 AAV 的血友病基因疗法可减少血友病患者的出血次数和因子输注次数,平均每年分别减少约 7 次和 103 次。分别有 80%、18% 和 63% 的血友病患者 TRAE、SAE 和 ALT 水平升高。此外,亚组分析发现,治疗 2-3 年后,ABR 和 AIR 显著下降。其他未汇总的结果(包括凝血因子活性)见附表。我们的分析证实了 AAV 介导的血友病基因疗法的有效性和安全性,为将来将其作为一种治疗方法广泛应用于血友病患者的临床治疗提供了证据。
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引用次数: 0
Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia. 白细胞介素-10转基因的慢性表达可调节心脏交感神经节,从而减少室性心律失常。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-02-06 DOI: 10.1089/hum.2023.160
Rui Li, Ling Zhang, Chen Peng, Yanmei Lu, Zhihao Liu, Xiao Xu, Changyi Wang, Ruijie Hu, Wuping Tan, Liping Zhou, Yueyi Wang, Lilei Yu, Yuhong Wang, Baopeng Tang, Hong Jiang

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

心脏自主神经系统(CANS)与心脏系统的电生理学和心律失常发生的调节密切相关。本研究旨在探讨白细胞介素-10(IL-10)能否通过长期作用于心脏交感神经节,有效调节心脏自律神经系统,抑制缺血诱发的室性心律失常。我们利用腺相关病毒,在心脏交感神经节--左星状神经节(LSG)局部实现了IL-10的慢性过量分泌。因此,在 IL-10 组中,我们观察到 LSG 中酪氨酸羟化酶阳性(TH+)细胞数量减少。IL-10 能明显下调神经生长因子、突触素和生长相关蛋白 43 的表达。体内动态心电图结果显示,IL-10过表达能显著抑制心脏交感神经系统的活动,改善心率变异性。同时,我们观察到IL-10组心肌梗死后LSG功能下降,心室有效折返期延长,室性心律失常得到抑制。此外,IL-10过表达可减轻急性心肌梗死后心肌的炎症反应并降低去甲肾上腺素水平。总之,我们的数据表明,慢性 IL-10 过度表达可调节心脏交感神经重塑,抑制心肌梗死诱发的室性心律失常。通过腺相关病毒介导的IL-10过表达进行神经调节可能具有潜在神经免疫疗法的特点和优势,可用于预防心肌梗死诱发的室性心律失常。
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引用次数: 0
Drug Repositioning for Amyloid Transthyretin Amyloidosis by Interactome Network Corrected by Graph Neural Networks and Transcriptome Analysis. 通过图形神经网络和转录组分析校正的相互作用组网络对ATTR淀粉样变性的药物重新定位。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-11-27 DOI: 10.1089/hum.2021.222
Shan He, XiaoYing Lv, XinYue He, JinJiang Guo, RuoKai Pan, YuTong Jin, Zhuang Tian, LuRong Pan, ShuYang Zhang

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.

淀粉样转甲状腺素(ATTR)淀粉样变性是由转甲状腺素在神经和心脏中错误折叠成淀粉样沉积物引起的一种进行性罕见疾病。发病机制不明,缺乏治疗,使5年生存预后极差。目前可用的ATTR药物只能缓解症状并减缓进展,但没有任何药物被证明对这种疾病有效。不断增长的药理学数据和大规模基因组和转录组数据为通过计算药物重新定位寻找潜在的新型ATTR药物带来了新的机会。我们分别从五个公共数据库和GEO表达谱中收集了与疾病发病机制相关的ATTR和差异表达(DE)基因,然后通过对ATTR相关基因和DrugBank数据库中的药物靶点进行校正蛋白质-蛋白质网络分析来筛选候选药物,然后基于受化合物干扰的基因表达数据过滤候选药物。我们分别从五个公共数据库和转录组数据中收集了139个和56个ATTR相关基因,并进行了功能富集分析。根据校正的相互作用组网络中ATTR相关基因的接近程度,我们筛选出355种候选药物,并通过图神经网络(GNN)进行了改进。反向基因集富集分析被进一步应用于估计扰动对ATTR相关和差异表达(DE)基因的影响。讨论了高概率候选药物。在具有转录组数据的相互作用组网络上使用系统计算过程进行药物重新定位,以筛选出几种潜在的ATTR新药候选药物。
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引用次数: 0
Advancing Precision Medicine with Gene and Cell Therapy in Malaysia: Ethical, Legal, and Social Implications. 推进精准医学与基因和细胞治疗在马来西亚:伦理,法律和社会影响(ELSI)。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-01-01 DOI: 10.1089/hum.2023.139
V Kalidasan, Kumitaa Theva Das

A new era of gene and cell therapy for treating human diseases has been envisioned for several decades. However, given that the technology can alter any DNA/cell in human beings, it poses specific ethical, legal, and social difficulties in its application. In Malaysia, current bioethics and medical ethics guidelines tackle clinical trials and biomedical research, medical genetic services, and stem cell research/therapy. However, no comprehensive framework and policy is available to cater to ethical gene and cell therapy in the country. Incorporating ethical, legal, and social implications (ELSI) would be crucial to guide the appropriate use of human gene and cell therapy in conjunction with precision medicine. Policy experts, scientists, bioethicists, and public members must debate the associated ELSI and the professional code of conduct while preserving human rights.

基因和细胞疗法治疗人类疾病的新时代已经被设想了几十年。然而,考虑到这项技术可以改变人类的任何DNA/细胞,它在应用中会带来特定的伦理、法律和社会困难。在马来西亚,目前的生物伦理和医学伦理准则涉及临床试验和生物医学研究、医学遗传服务以及干细胞研究/治疗。然而,该国没有全面的框架和政策来迎合伦理基因和细胞治疗。结合伦理、法律和社会影响(ELSI)将是指导人类基因和细胞治疗与精准医学相结合的适当使用的关键。政策专家、科学家、生物伦理学家和公众成员必须在维护人权的同时,就相关的ELSI和专业行为准则进行辩论。
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引用次数: 0
CASGEVY Makes History as FDA Approves First CRISPR/Cas9 Genome Edited Therapy. CASGEVY 创造历史,FDA 批准首个 CRISPR/Cas9 基因组编辑疗法。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-01-01 DOI: 10.1089/hum.2023.29263.bfs
Alex Philippidis
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引用次数: 0
Prophylactic Prednisolone Promotes AAV5 Hepatocyte Transduction Through the Novel Mechanism of AAV5 Coreceptor Platelet-Derived Growth Factor Receptor Alpha Upregulation and Innate Immune Suppression. 预防性泼尼松龙通过 AAV5 共受体 PDGFRα 上调和先天性免疫抑制的新机制促进 AAV5 肝细胞转导。
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-01-01 DOI: 10.1089/hum.2023.065
Britta Handyside, Lening Zhang, Bridget Yates, Lin Xie, Ashrafali Mohamed Ismail, Ryan Murphy, Brian Baridon, Cheng Su, Taren Bouwman, Linley Mangini, Jorden Tahquechi, Sandra Salcido, Wesley C Minto, William T Keenan, Ioanna Ntai, Choong-Ryoul Sihn, Sherry Bullens, Stuart Bunting, Sylvia Fong

Adeno-associated virus (AAV) vectors are used to deliver therapeutic transgenes, but host immune responses may interfere with transduction and transgene expression. We evaluated prophylactic corticosteroid treatment on AAV5-mediated expression in liver tissue. Wild-type C57BL/6 mice received 6 × 1013 vg/kg AAV5-HLP-hA1AT, an AAV5 vector carrying a human α1-antitrypsin (hA1AT) gene with a hepatocyte-specific promoter. Mice received 4 weeks of daily 2 mg/kg prednisolone or water starting day -1 or 0 before vector dosing. Mice that received prophylactic corticosteroids had significantly higher serum hA1AT protein than mice that did not, starting at 6 weeks and persisting to the study end at 12 weeks, potentially through a decrease in the number of low responders. RNAseq and proteomic analyses investigating mechanisms mediating the improvement of transgene expression found that prophylactic corticosteroid treatment upregulated the AAV5 coreceptor platelet-derived growth factor receptor alpha (PDGFRα) on hepatocytes and downregulated its competitive ligand PDGFα, thus increasing the uptake of AAV5 vectors. Evidently, prophylactic corticosteroid treatment also suppressed acute immune responses to AAV. Together, these mechanisms resulted in increased uptake and preservation of the transgene, allowing more vector genomes to be available to assemble into stable, full-length structures mediating long-term transgene expression. Prophylactic corticosteroids represent a potential actionable strategy to improve AAV5-mediated transgene expression and decrease intersubject variability.

腺相关病毒(AAV)载体用于传递治疗性转基因,但宿主免疫反应可能会干扰转导和转基因表达。我们评估了预防性皮质类固醇治疗对 AAV5 介导的肝组织表达的影响。野生型 C57BL/6 小鼠接受了 6x1013 vg/kg AAV5-HLP-hA1AT,这是一种携带有肝细胞特异性启动子的人α1-抗胰蛋白酶(hA1AT)基因的 AAV5 载体。小鼠从载体给药前的第1天或第0天开始,每天接受2毫克/千克泼尼松龙或水治疗4周。与未接受预防性皮质类固醇治疗的小鼠相比,接受预防性皮质类固醇治疗的小鼠血清中的 hA1AT 蛋白含量明显较高,从 6 周开始持续到 12 周研究结束,这可能是由于低应答者的数量减少所致。研究转基因表达改善机制的RNAseq和蛋白质组学分析发现,预防性皮质类固醇治疗可上调肝细胞上的AAV5共受体血小板衍生生长因子受体α(PDGFRα),并下调其竞争配体PDGFα,从而增加AAV5载体的吸收。显然,预防性皮质类固醇治疗也抑制了对 AAV 的急性免疫反应。这些机制共同作用,增加了转基因的吸收和保存,使更多的载体基因组能够组装成稳定的全长结构,从而促进转基因的长期表达。预防性使用皮质类固醇是改善 AAV5 介导的转基因表达和降低受试者间变异性的潜在可行策略。
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引用次数: 0
Prevalence of Adeno-Associated Virus-9-Neutralizing Antibody in Chinese Patients with Duchenne Muscular Dystrophy. 中国杜氏肌营养不良症患者的腺相关病毒-9中和抗体流行率
IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-12-27 DOI: 10.1089/hum.2023.117
Cuijie Wei, Dongliang Li, Meng Zhang, Yanping Zhao, Yidan Liu, Yanbin Fan, Lu Wang, Jieyu Liu, Xingzhi Chang, Yuwu Jiang, Hui Xiong

The delivery of a mini-dystrophin gene to skeletal muscles using recombinant adeno-associated virus serotype (AAV) holds great potential as a gene therapy for Duchenne muscular dystrophy (DMD). However, the presence of anti-AAV-neutralizing antibodies (NAbs) may impede the effectiveness of gene transduction. This study aimed to evaluate the prevalence of anti-AAV9 NAbs in Chinese patients with DMD, and to characterize the target population for an AAV gene therapy. A total of one hundred male patients with DMD were included in this study, and demographic and clinical data were collected. A blood specimen was obtained from each participant for the purpose of evaluating the existence of anti-AAV9 NAbs through a cell-based functional assay conducted at a central laboratory. A NAb titer exceeding 1:4 was considered positive. The positivity rates of anti-AAV9 NAb were compared among different subgroups. The median age of this DMD cohort was 8 years old, ranging from 3 to 15 years of age. Forty-two percent of patients tested positive for anti-AAV9 NAb. Notably, all samples from patients under 4 years of age tested negative, and the positivity rates of anti-AAV9 NAb differed significantly across the three age subgroups (<4 years old, ≥4 years old and <12 years old, and ≥12 years old, χ2 = 7.221, p = 0.023). Further investigation into the living environment revealed a higher positivity rate of anti-AAV9 NAb in rural patients compared with urban patients (χ2 = 3.923, p = 0.048). Moreover, the prevalence in patients from different cities/provinces varied greatly (χ2 = 16.550, p = 0.003). There was no statistically significant difference in the positivity rate of NAb among subgroups of patients with different motor functions (ambulatory or nonambulatory) and different treatment strategies (taking or not taking glucocorticoid). In Chinese DMD patients, the prevalence of anti-AAV9 NAb was found to reach 42%. Moreover, the antibody-positive rate in children <4 years of age was low and revealed notable regional discrepancies.

目的:利用重组腺相关病毒血清型(AAV)向骨骼肌输送微型肌营养不良蛋白基因,作为治疗杜兴氏肌肉萎缩症(DMD)的基因疗法具有巨大潜力。然而,抗 AAV 中和抗体(NAbs)的存在可能会阻碍基因转导的有效性。本研究旨在评估抗AAV9 NAbs在中国DMD患者中的流行率,并确定AAV基因治疗目标人群的特征:方法:本研究共纳入 100 名男性 DMD 患者,并收集了他们的人口统计学和临床数据。从每位患者身上采集血液标本,以便在中心实验室通过细胞功能检测评估抗 AAV9 中和抗体的存在。NAb 滴度超过 1:4 即为阳性。比较了不同亚组的抗AAV9 NAb阳性率:该 DMD 群体的中位年龄为 8 岁,从 3 岁到 15 岁不等。42% 的患者抗 AAV9 NAb 检测呈阳性。值得注意的是,4岁以下患者的所有样本检测结果均为阴性,且三个年龄亚组的抗AAV9 NAb阳性率差异显著:在中国的 DMD 患者中,抗 AAV9 NAb 阳性率高达 42%。此外,4 岁以下儿童的抗体阳性率较低,且存在明显的地区差异。
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Human gene therapy
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