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Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide SPL84吸入反义寡核苷酸的递送特性
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-11 DOI: 10.1101/2023.01.09.23284328
E. Ozeri-Galai, L. Friedman, O. Barchad-Avitzur, M. Markovetz, W. Boone, K. Rouillard, Chava D Stampfer, Y. Oren, D. Hill, B. Kerem, G. Hart
The last years have shown enormous advancement in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, leading to increased numbers of ASO regulatory approvals. In this study we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease, Cystic Fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when aiming to target the cell nucleus. The efficient distribution of SPL84 in the lungs, penetration into the cells and nucleus, and stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate the proper distribution and cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability and mobility of our inhaled ASO drug through CF patient-derived mucus and in lung lysosomal extracts. Our results, supported by a promising pre-clinical pharmacological effect, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 and specific cell targeting offers huge opportunities for further development of SpliSense inhaled ASO-based drugs for unmet pulmonary diseases.
近年来,RNA相关治疗的治疗潜力取得了巨大进展,特别是基于反义寡核苷酸(ASO)的药物,导致ASO监管批准的数量增加。在这项研究中,我们重点关注SPL84,这是一种基于ASO的吸入性药物,用于治疗肺部疾病囊性纤维化(CF)。由于存在各种生物、物理、化学和结构障碍,尤其是在靶向细胞核时,肺部给药具有挑战性。SPL84在肺部的有效分布、对细胞和细胞核的渗透以及稳定性是影响临床疗效的关键参数。在这项研究中,我们证明了SPL84在小鼠和猴子肺中的正确分布以及细胞和细胞核的穿透。体内和体外研究证实了我们吸入的ASO药物通过CF患者来源的粘液和肺溶酶体提取物的稳定性和流动性。我们的研究结果得到了有前景的临床前药理作用的支持,强调了SPL84作为治疗CF患者的有效药物的高潜力。此外,成功解决SPL84的肺部分布和特异性细胞靶向为进一步开发基于SpliSense吸入ASO的药物治疗未满足的肺部疾病提供了巨大机会。
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引用次数: 4
Knockdown of Circular RNAs Using LNA-Modified Antisense Oligonucleotides. 利用rna修饰的反义寡核苷酸敲低环状rna。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0040
Marianne Bengtson Løvendorf, Anja Holm, Andreas Petri, Charlotte Albæk Thrue, Shizuka Uchida, Morten T Venø, Sakari Kauppinen

Circular RNAs (circRNAs) constitute an abundant class of covalently closed noncoding RNA molecules that are formed by backsplicing from eukaryotic protein-coding genes. Recent studies have shown that circRNAs can act as microRNA or protein decoys, as well as transcriptional regulators. However, the functions of most circRNAs are still poorly understood. Because circRNA sequences overlap with their linear parent transcripts, depleting specific circRNAs without affecting host gene expression remains a challenge. In this study, we assessed the utility of LNA-modified antisense oligonucleotides (ASOs) to knock down circRNAs for loss-of-function studies. We found that, while most RNase H-dependent gapmer ASOs mediate effective knockdown of their target circRNAs, some gapmers reduce the levels of the linear parent transcript. The circRNA targeting specificity can be enhanced using design-optimized gapmer ASOs, which display potent and specific circRNA knockdown with a minimal effect on the host genes. In summary, our results demonstrate that LNA-modified ASOs complementary to backsplice-junction sequences mediate robust knockdown of circRNAs in vitro and, thus, represent a useful tool to explore the biological roles of circRNAs in loss-of-function studies in cultured cells and animal models.

环状RNA (circRNAs)是一类丰富的共价封闭非编码RNA分子,由真核蛋白编码基因反剪接形成。最近的研究表明,circRNAs可以作为microRNA或蛋白质诱饵,以及转录调节因子。然而,大多数circrna的功能仍然知之甚少。由于circRNA序列与其线性亲本转录物重叠,在不影响宿主基因表达的情况下消耗特定的circRNA仍然是一个挑战。在这项研究中,我们评估了rna修饰的反义寡核苷酸(ASOs)在功能丧失研究中敲低环状rna的效用。我们发现,虽然大多数依赖RNase h的间隙子ASOs介导其靶环状rna的有效敲低,但一些间隙子降低了线性亲本转录物的水平。使用设计优化的gapmer ASOs可以增强circRNA靶向特异性,这些ASOs显示出有效和特异性的circRNA敲除,对宿主基因的影响最小。总之,我们的研究结果表明,与后剪接连接序列互补的na修饰ASOs在体外介导环状rna的强敲低,因此,在培养细胞和动物模型中探索环状rna在功能丧失研究中的生物学作用是一种有用的工具。
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引用次数: 1
Acknowledgment of Reviewers 2022. 审稿人致谢2022。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.29006.ack
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引用次数: 0
Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy. 在杜氏肌营养不良小鼠模型中,经结合sirna全身治疗后骨骼肌中Alk4的有效下调
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0021
Sarah Engelbeen, Svetlana Pasteuning-Vuhman, Joke Boertje-van der Meulen, Rubina Parmar, Klaus Charisse, Laura Sepp-Lorenzino, Muthiah Manoharan, Annemieke Aartsma-Rus, Maaike van Putten

Downregulation of genes involved in the secondary pathology of Duchenne muscular dystrophy, for example, inflammation, fibrosis, and adiposis, is an interesting approach to ameliorate degeneration of muscle and replacement by fibrotic and adiposis tissue. Small interfering RNAs (siRNAs) are able to downregulate target genes, however, delivery of siRNAs to skeletal muscle still remains a challenge. We investigated delivery of fully chemically modified, cholesterol-conjugated siRNAs targeting Alk4, a nontherapeutic target that is expressed highly in muscle. We observed that a single intravenous or intraperitoneal (IP) injection of 10 mg/kg resulted in significant downregulation of Alk4 mRNA expression in skeletal muscles in both wild-type and mdx mice. Treatment with multiple IP injections of 10 mg/kg led to an overall reduction of Alk4 expression, reaching significance in tibialis anterior (39.7% ± 6.2%), diaphragm (32.7% ± 5.8%), and liver (41.3% ± 29.9%) in mdx mice. Doubling of the siRNA dose did not further increase mRNA silencing in muscles of mdx mice. The chemically modified conjugated siRNAs used in this study are very promising for delivery to both nondystrophic and dystrophic muscles and could have major implications for treatment of muscular dystrophy pathology.

下调参与杜氏肌营养不良继发病理(如炎症、纤维化和脂肪化)的基因是改善肌肉退行性变和纤维化和脂肪组织替代的有趣途径。小干扰rna (sirna)能够下调靶基因,然而,将sirna递送到骨骼肌仍然是一个挑战。我们研究了完全化学修饰的胆固醇偶联sirna靶向Alk4的递送,Alk4是一种在肌肉中高度表达的非治疗性靶标。我们观察到,单次静脉注射或腹腔注射10 mg/kg可显著下调野生型和mdx小鼠骨骼肌中Alk4 mRNA的表达。多次注射10 mg/kg的IP可使mdx小鼠的胫骨前肌(39.7%±6.2%)、膈肌(32.7%±5.8%)和肝脏(41.3%±29.9%)的Alk4表达全面降低。siRNA剂量加倍并没有进一步增加mdx小鼠肌肉中mRNA的沉默。本研究中使用的化学修饰的共轭sirna非常有希望用于非营养不良和营养不良肌肉的递送,并且可能对肌肉营养不良病理的治疗具有重要意义。
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引用次数: 3
Cholesterol-Conjugated siRNA Silencing Tnf for the Treatment of Liver Macrophage-Mediated Acute Inflammation in Nonalcoholic Fatty Liver Disease. 胆固醇偶联siRNA沉默Tnf治疗非酒精性脂肪肝中肝巨噬细胞介导的急性炎症
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0038
Kevin Craig, Marc Abrams, Mansoor Amiji

Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoholic fatty liver disease (NAFLD) remain elusive. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease resolution. Mounting preclinical evidence indicates liver inflammation may play a major role in steatosis development and fibrosis but has not garnered the same clinical representation. This may be owing to deficiencies in standard therapeutic modalities that limit their application in NAFLD. RNA interference (RNAi) is an attractive approach to targeting liver inflammation owing to its clinical safety profile, target specificity, and limited biodistribution. In this study, we characterize a simple cholesterol-short-interfering RNA (siRNA) conjugate system targeting Tnf mRNA in liver macrophages for the treatment of NAFLD. First, we observed delivery and anti-inflammatory activity in an acute liver inflammation model. In a follow-up murine NAFLD model, we observed total prevention of nearly all hallmarks of this disease: steatosis, inflammation, and fibrosis. This simple conjugate siRNA delivery system may be the first to show RNAi activity in liver macrophages and provide evidence for a novel therapeutic approach to inflammation in NAFLD.

尽管非酒精性脂肪性肝病(NAFLD)被广泛认为是一种流行病,但有效的治疗方法仍然难以捉摸。目前大多数临床项目旨在减少肝脏脂肪堆积,从而预防下游炎症和纤维化。迄今为止,这种治疗方法已经帮助确定了脂肪变性减少和疾病解决之间的潜在脱节。越来越多的临床前证据表明,肝脏炎症可能在脂肪变性和纤维化的发展中起主要作用,但尚未获得相同的临床表现。这可能是由于标准治疗方式的缺陷限制了其在NAFLD中的应用。RNA干扰(RNAi)由于其临床安全性、靶向特异性和有限的生物分布,是一种有吸引力的靶向肝脏炎症的方法。在这项研究中,我们描述了一个简单的胆固醇-短干扰RNA (siRNA)偶联系统靶向肝巨噬细胞Tnf mRNA治疗NAFLD。首先,我们观察了急性肝脏炎症模型的传递和抗炎活性。在后续的小鼠NAFLD模型中,我们观察到几乎完全预防了这种疾病的所有特征:脂肪变性、炎症和纤维化。这种简单的偶联siRNA递送系统可能是第一个在肝巨噬细胞中显示RNAi活性的系统,并为NAFLD炎症的新治疗方法提供证据。
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引用次数: 0
Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides. 反义寡核苷酸临床前安全性评估的考虑。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0061
Aurélie Goyenvalle, Cecilia Jimenez-Mallebrera, Willeke van Roon, Sabine Sewing, Arthur M Krieg, Virginia Arechavala-Gomeza, Patrik Andersson

The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network "DARTER," a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.

在过去的几十年里,核酸治疗领域取得了巨大的进步。化学和设计的不断进步导致了许多成功的临床应用,引起了包括学术团体和药物开发公司在内的研究人员的更多兴趣。该领域的许多临床前研究侧重于改善反义寡核苷酸药物(ond)的递送和/或评估其在靶组织中的功效,通常忽略了毒性评估,至少在开发的早期阶段。国际人用药品技术要求协调理事会(WGS6)的寡核苷酸安全工作组和日本研究工作组在几份白皮书中提出了一系列关于监管考虑和期望的共识建议。然而,在筛选和设计OND的早期阶段,也应该考虑安全性方面的问题,以避免在开发阶段出现后续故障。由欧盟科学技术合作资助的成本行动“DARTER”网络的专家和成员利用他们与OND合作的集体经验,以及他们对OND介导的毒性的见解,产生了一系列共识建议,以评估临床前研究早期阶段的OND毒性。在过去的几年里,一些出版物描述了预测分析,可用于评估ond介导的体外或离体毒性,在进入临床前开发的体内阶段(即动物毒性研究)之前过滤掉潜在的候选毒性。这些检测也有可能提供翻译的见解,因为它们允许在人类体外系统的安全性评估。然而,也应该考虑进行小型的初步体内研究,以补充这种早期评估。在本研究中,我们总结了目前的技术状况,并提供了用于这些早期临床前评估的不同测试的指南和建议。
{"title":"Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.","authors":"Aurélie Goyenvalle,&nbsp;Cecilia Jimenez-Mallebrera,&nbsp;Willeke van Roon,&nbsp;Sabine Sewing,&nbsp;Arthur M Krieg,&nbsp;Virginia Arechavala-Gomeza,&nbsp;Patrik Andersson","doi":"10.1089/nat.2022.0061","DOIUrl":"https://doi.org/10.1089/nat.2022.0061","url":null,"abstract":"<p><p>The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network \"DARTER,\" a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity <i>in vitro</i> or <i>ex vivo</i> to filter out potential toxic candidates before moving to <i>in vivo</i> phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human <i>in vitro</i> systems. Yet, small preliminary <i>in vivo</i> studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 1","pages":"1-16"},"PeriodicalIF":4.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 8
Elevation of SHANK3 Levels by Antisense Oligonucleotides Directed Against the 3'-UTR of the Human SHANK3 mRNA. 针对人SHANK3 mRNA 3'-UTR的反义寡核苷酸提高SHANK3水平
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0048
Nadine Stirmlinger, Jan Philipp Delling, Stefanie Pfänder, Tobias M Boeckers

SHANK3 is a member of the SHANK family of scaffolding proteins that localize to the postsynaptic density of excitatory synapses. Mutations within the SHANK3 gene or SHANK3 haploinsufficiency is thought to be one of the major causes for Phelan-McDermid Syndrome (PMDS) that is characterized by a broad spectrum of autism-related behavioral alterations. Several approaches have already been proposed to elevate SHANK3 protein levels in PMDS patients like transcriptional activation or inhibition of SHANK3 degradation. We undertook a systematic screening approach and tested whether defined antisense oligonucleotides (ASOs) directed against the 3' untranslated region (3'-UTR) of the human SHANK3 mRNA are suitable to elevate SHANK3 protein levels. Using human induced pluripotent stem cells (hiPSCs) and hiPSCs-derived motoneurons from controls and PMDS patients we eventually identified two 18 nucleotide ASOs (ASO 4-5.2-4 and 4-5.2-6) that were able to increase SHANK3 protein levels in vitro by about 1.3- to 1.6-fold. These findings were confirmed by co-transfection of the identified ASOs with a GFP-SHANK3-3'-UTR construct in HEK293T cells using GFP protein expression as read-out. Based on these results we propose a novel approach to elevate SHANK3 protein concentrations by 3'-UTR specific ASOs. Further research is needed to test the suitability of SHANK3-specific ASOs as pharmacological compounds also in vivo.

SHANK3是SHANK支架蛋白家族的成员,定位于兴奋性突触的突触后密度。SHANK3基因突变或SHANK3单倍不全被认为是导致Phelan-McDermid综合征(PMDS)的主要原因之一,该综合征以广泛的自闭症相关行为改变为特征。已经提出了几种方法来提高PMDS患者的SHANK3蛋白水平,如转录激活或抑制SHANK3降解。我们采用了系统的筛选方法,并测试了针对人类SHANK3 mRNA 3'非翻译区(3'-UTR)的特定反义寡核苷酸(ASOs)是否适合提高SHANK3蛋白水平。利用来自对照和PMDS患者的人诱导多能干细胞(hiPSCs)和hiPSCs衍生的运动神经元,我们最终鉴定出两个18个核苷酸的ASO (ASO 4-5.2-4和4-5.2-6),它们能够将体外SHANK3蛋白水平提高约1.3- 1.6倍。在HEK293T细胞中,用GFP- shank3 -3'-UTR构建体共转染鉴定的ASOs,以GFP蛋白表达为读出,证实了这些发现。基于这些结果,我们提出了一种通过3'-UTR特异性ASOs提高SHANK3蛋白浓度的新方法。尚需进一步研究shank3特异性ASOs作为体内药理化合物的适用性。
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引用次数: 1
Consensus Guidelines for the Design and In Vitro Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides. N-of-1外显子跳跃反义寡核苷酸设计和体外临床前疗效检测的共识指南。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1089/nat.2022.0060
Annemieke Aartsma-Rus, Alejandro Garanto, Willeke van Roon-Mom, Erin M McConnell, Victoria Suslovitch, Winston X Yan, Jonathan K Watts, Timothy W Yu

Antisense oligonucleotides (ASOs) can modulate pre-mRNA splicing. This offers therapeutic opportunities for numerous genetic diseases, often in a mutation-specific and sometimes even individual-specific manner. Developing therapeutic ASOs for as few as even a single patient has been shown feasible with the development of Milasen for an individual with Batten disease. Efforts to develop individualized ASOs for patients with different genetic diseases are ongoing globally. The N = 1 Collaborative (N1C) is an umbrella organization dedicated to supporting the nascent field of individualized medicine. N1C recently organized a workshop to discuss and advance standards for the rigorous design and testing of splice-switching ASOs. In this study, we present guidelines resulting from that meeting and the key recommendations: (1) dissemination of standardized experimental designs, (2) use of standardized reference ASOs, and (3) a commitment to data sharing and exchange.

反义寡核苷酸(ASOs)可以调节前mrna剪接。这为许多遗传疾病提供了治疗机会,通常是针对突变的,有时甚至是针对个体的。随着Milasen在巴滕病患者身上的发展,为单个患者开发治疗性aso已被证明是可行的。全球正在努力为不同遗传疾病的患者开发个性化的aso。N = 1协作组织(N1C)是一个伞形组织,致力于支持新兴的个体化医学领域。N1C最近组织了一个研讨会,讨论和推进拼接开关ASOs的严格设计和测试标准。在本研究中,我们提出了该会议产生的指导方针和主要建议:(1)传播标准化实验设计,(2)使用标准化参考aso,(3)承诺数据共享和交换。
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引用次数: 5
Integrated Assessment of Phase 2 Data on GalNAc3-Conjugated 2'-O-Methoxyethyl-Modified Antisense Oligonucleotides. GalNAc3缀合的2'-O-甲氧基乙基修饰的反义寡核苷酸的2期数据的综合评估。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2022-11-29 DOI: 10.1089/nat.2022.0044
Brenda F Baker, Shuting Xia, Wesley Partridge, T Jesse Kwoh, Sotirios Tsimikas, Sanjay Bhanot, Richard S Geary

Receptor-mediated delivery of an antisense oligonucleotide (ASO) using the ligand-conjugated antisense technology is establishing a new benchmark for antisense therapeutics. The triantennary N-acetylgalactosamine (GalNAc3) cluster is the first conjugated ligand to yield a marked increase in ASO potency for RNA targets expressed by hepatocytes, compared to the unconjugated form. In this study, we present an integrated safety assessment of data available from randomized, placebo-controlled, phase 2 studies for six GalNAc3-conjugated 2'-O-methoxyethyl (2'MOE)-modified ASOs. The total study population included 642 participants (130 placebo; 512 ASO) with up to 1 year of exposure. The primary measures were the incidence of signals from standardized laboratory tests and the mean test results over time. The GalNAc3-conjugated ASOs were well tolerated with no class effect identified across all doses tested compared to placebo. These results extend prior observations from phase 1 studies, now with treatment up to 1 year.

受体介导的使用配体偶联的反义技术的反义寡核苷酸(ASO)的递送为反义疗法建立了一个新的基准。与非偶联形式相比,三元N-乙酰氨基半乳糖(GalNAc3)簇是第一个对肝细胞表达的RNA靶标产生ASO效力显著提高的偶联配体。在这项研究中,我们对随机、安慰剂对照、,六个GalNAc3偶联的2'-O-甲氧基乙基(2'MOE)修饰的ASO的2期研究。总研究人群包括642名暴露时间长达1年的参与者(130名安慰剂;512名ASO)。主要测量指标是标准化实验室测试的信号发生率和一段时间内的平均测试结果。与安慰剂相比,GalNAc3偶联的ASOs耐受性良好,在所有测试剂量中均未发现类别效应。这些结果扩展了先前1期研究的观察结果,现在治疗长达1年。
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引用次数: 4
Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated siRNAs. galnac偶联sirna的生物期半衰期和效力的跨物种翻译。
IF 4 2区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-01 DOI: 10.1089/nat.2022.0010
Alessandro Boianelli, Yasunori Aoki, Maxim Ivanov, Anders Dahlén, Peter Gennemark

Small interfering RNAs (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for in vivo study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.

小干扰rna (sirna)与n -乙酰半乳糖胺(GalNAc)偶联改善肝脏摄取是一类治疗肝脏疾病的新兴药物。了解药代动力学和药效学如何转化是体内研究设计和人体剂量预测的关键。然而,关于这种方式的翻译数据的文献很少,并且很少测量肝脏中的药代动力学。为了克服这些困难,我们收集了不同物种中11种galnac - sirna的时间过程生物标志物数据,并应用动力学药效学建模方法来估计生物期(肝脏)半衰期和效力。结果表明,小鼠的半衰期为0.6-3周,猴的半衰期为1-8周,人的半衰期为1.5-14周。对于单个sirna,人类的生物期半衰期是小鼠的1-8倍,一般是猴子的1-3倍。分析表明,sirna在人体内比在小鼠和猴子体内更有效。
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引用次数: 2
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Nucleic acid therapeutics
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