This is a phase 1b/2 open-label, multicenter, basket study to determine the safety, anti-tumor activity, tolerability, and pharmacokinetics /pharmacodynamics of AsiDNA in combination with olaparib in participants with recurrent epithelial ovarian cancer, breast cancer and metastatic castration-resistant prostate cancer who have progressed on previous Poly (ADP-ribose) polymerase (PARP) inhibitor therapy. The study will be conducted in two phases. The Phase 1b dose escalation study designed to establish the safety, tolerability, pharmacologically active doses/ maximum tolerated dose and/or recommended phase 2 dose of AsiDNA in combination with olaparib.

开始日期2023-02-20

申办/合作机构

Valerio Therapeutics SA

NCT05394558 / Terminated临床1/2期IIT

A Phase Ib/II Study on AsiDNA in Association With Re-irradiation in Children, Adolescents and Young Adults With High-grade Glioma

HGG comprises diffuse midline gliomas (DMG), including diffuse infiltrating brainstem glioma (DIPG), characterised by histone gene mutations, as well as non-DM HGGs mainly in non-midline supratentorial areas, with distinct molecular abnormalities. First-line treatment comprises surgery when doable (non-DM HGGs), and radiotherapy in all cases. Chemotherapy or other drugs in clinical trials may be added during and/or after radiotherapy depending on the HGG subtype. The recurrence rate is nevertheless high in all paediatric and adolescent HGGs. If the time interval between the end of first-line radiotherapy and relapse is long enough, re-irradiation often provides good palliation of symptoms, delays disease progression, improves quality of life and has minimal and manageable toxicity. Nevertheless, strategies to increase efficacy without increasing toxicity in the treatment of recurrent paediatric HGG are much needed.
AsiDNA™ is a DNA repair inhibitor that increases the vulnerability of tumour cells to irradiation without increasing toxicity in healthy tissues. Its novel mechanism of action, based on perturbation of the DNA damage recognition steps in DNA repair, makes its activity specific to tumour cells. Intravenous administration of AsiDNA is currently being investigated in adults with advanced solid tumours. The MTD was not reached during the escalating dose study on the safety, pharmacokinetics and pharmacodynamics of AsiDNA administered as a 1-hour infusion, however an optimal dose range (400-600 mg) was identified for further development, based on the favourable safety and PK profiles. Preclinical studies on AsiDNA added to radiotherapy have shown increased survival and no increase in short- or long-term toxicity due to the high doses of irradiation.
The study will provide paediatric patients who have recurrent HGG with early access to innovation, even during the early drug development stage in adults.

开始日期2022-05-27

申办/合作机构

Institut Curie

NCT04826198 / Recruiting临床1/2期IIT

An Open-label, Multicentric, Phase Ib/II Study to Assess the Safety and Efficacy of AsiDNATM, a DNA Repair Inhibitor, Administered Intravenously in Addition to Niraparib in Patients With Relapsed Platinum Sensitive Ovarian Cancer Already Treated With Niraparib Since at Least 6 Months

The objective of REVOCAN study is to assess the abrogation of PARP inhibitors resistance in patients with relapsed platinum sensitive ovarian cancer treated with PARP inhibitors in maintenance since at least 6 months and who have only an increase of CA 125 without any progression according to RECIST criteria. AsiDNATM at 600 mg will be tested in addition to PARP inhibitors given according to the label in REVOCAN study.

开始日期2020-10-05

申办/合作机构

Institut Gustave Roussy EURL

100 项与 Etidaligide 相关的临床结果

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100 项与 Etidaligide 相关的转化医学

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100 项与 Etidaligide 相关的专利（医药）

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项与 Etidaligide 相关的文献（医药）

2024-10-01·Cell

Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function

Article

作者: McEwan, William A ; Sweeney, Paul W. ; Sanford, Sophie A.I. ; Higginson, Katie ; Katsinelos, Taxiarchis ; Miller, Lauren V C ; Benn, Jonathan ; Joyner, Holly ; James, Leo C ; Smith, Annabel ; James, Leo C. ; Sweeney, Paul W ; Papa, Guido ; Sanford, Sophie A I ; Huang, Melissa ; Franco, Catarina ; Cheng, Shi ; Miller, Lauren V.C. ; Farnsworth, Jasmine ; McEwan, William A. ; Vaysburd, Marina

Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called "RING-Bait," which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates its E3 function, resulting in the degradation of the aggregate complex. We exemplify this concept by demonstrating the specific degradation of tau aggregates while sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell-autonomous aggregation. RING-Bait removed tau aggregates seeded from Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) brain extracts and was also effective in primary neurons. We used a brain-penetrant adeno-associated virus (AAV) to treat P301S tau transgenic mice, reducing tau pathology and improving motor function. A RING-Bait strategy could be applied to other neurodegenerative proteinopathies by replacing the Bait sequence to match the target aggregate.

2024-03-01·Molecular Plant

Dt1 inhibits SWEET-mediated sucrose transport to regulate photoperiod-dependent seed weight in soybean

Article

作者: Liu, Hongjie ; Yang, Yuhua ; Yu, Bin ; Yao, Xiani ; Zhang, Chunyu ; Li, Haiyang ; Kong, Fanjiang ; Chen, Zhonghui ; Yue, Lin ; Huang, Xiang ; Hou, Xingliang ; Tan, Cuirong ; Liu, Baohui ; Li, Xiaoming ; Guan, Yuefeng ; Kong, Lingping ; Hu, Yilong

Soybean is a photoperiod-sensitive short-day crop whose reproductive period and yield are markedly affected by day-length changes. Seed weight is one of the key traits determining the soybean yield; however, the prominent genes that control the final seed weight of soybean and the mechanisms underlying the photoperiod's effect on this trait remain poorly understood. In this study, we identify SW19 as a major locus controlling soybean seed weight by QTL mapping and determine Dt1, an orthologous gene of Arabidopsis TFL1 that is known to govern the soybean growth habit, as the causal gene of the SW19 locus. We showed that Dt1 is highly expressed in developing seeds and regulates photoperiod-dependent seed weight in soybean. Further analyses revealed that the Dt1 protein physically interacts with the sucrose transporter GmSWEET10a to negatively regulate the import of sucrose from seed coat to the embryo, thus modulating seed weight under long days. However, Dt1 does not function in seed development under short days due to its very low expression. Importantly, we discovered a novel natural allelic variant of Dt1 (H4 haplotype) that decouples its pleiotropic effects on seed size and growth habit; i.e., this variant remains functional in seed development but fails to regulate the stem growth habit of soybean. Collectively, our findings provide new insights into how soybean seed development responds to photoperiod at different latitudes, offering an ideal genetic component for improving soybean's yield by manipulating its seed weight and growth habit.

2024-01-09·NAR Cancer

The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest

Article

作者: Girard, Pierre-Marie ; Berthault, Nathalie ; Fouillade, Charles ; Jdey, Wael ; Dubail, Maxime ; Petersson, Kristoffer ; Sesink, Anouk ; Heinrich, Sophie ; Becerra, Margaux ; Ruan, Jia-Ling ; Dutreix, Marie ; Leboucher, Sophie

AbstractAsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.

项与 Etidaligide 相关的新闻（医药）

2024-09-20

·生物谷

1篇Cell+1篇Science | 基于TRIM21 的“特洛伊木马疗法”，可靶向清除脑细胞中的tau蛋白聚集物，小鼠重现活力

科学家们开发出了一种新的潜在疗法，可以选择性地清除与阿尔茨海默病相关的tau蛋白聚集物，并改善小鼠的神经退行性症状。来自英国医学研究理事会（MRC）分子生物学实验室和剑桥大学英国痴呆症研究所的研究人员表示，这种方法未来也可能应用于其他由细胞内蛋白质聚集引起的脑部疾病，如运动神经元疾病、亨廷顿病和帕金森病。在发表于Cell和Science期刊上的两篇论文中，研究者展示了如何利用一种名为TRIM21的蛋白质的独特功能，为这种潜在疗法带来两个关键优势。首先，这种疗法只破坏与疾病相关的tau蛋白聚集物，而不破坏健康的tau蛋白。其次，它能清除小鼠体内已经形成的tau聚集物，而不仅仅是防止新的tau聚集物形成。 tau蛋白与阿尔茨海默病在阿尔茨海默病患者的大脑中，tau蛋白和淀粉样蛋白是两种主要的错误折叠并积聚成聚集物的蛋白质。淀粉样蛋白聚集物形成于脑细胞之间的空隙中，新型抗体疗法（如lecanemab）正靶向这些空隙进行治疗。相比之下，tau“缠结物”主要在神经细胞内形成，尽管它们可以在细胞间扩散，但随着疾病的进展，这与认知能力下降密切相关。抗体疗法很难接触到细胞内的tau蛋白，因此无法清除细胞内现有的tau聚集物，最多只能阻止这些聚集物扩散。其他靶向细胞内tau的技术，如反义寡核苷酸（ASO），已在早期临床试验中证明可以减少tau，但它们作用于大脑中的所有tau蛋白，因此也会清除“健康”的tau蛋白，其长期副作用尚不清楚。“健康”的tau蛋白通常为大脑神经细胞提供结构支持，起到支架的作用。利用TRIM21清除tau聚集物这种靶向tau缠结物的新技术利用了MRC分子生物学实验室Leo James博士实验室在2010年发现的一种名为TRIM21的蛋白质的独特功能。TRIM21通常在细胞外与入侵病毒结合的抗体进入细胞时，检测并标记病毒为“垃圾”，交由细胞的“垃圾处理工厂”蛋白酶体进行破坏。图片来自Cell, 2024, doi:10.1016/j.cell.2024.08.024 2023年，同一研究团队证实TRIM21可以重新用于破坏与阿尔茨海默病相关的tau蛋白聚集物（Science, 2023, doi:10.1126/science.abn1366）。通过将结合病毒的抗体换成结合tau的抗体，TRIM21被重新定向，将tau聚集物送往蛋白酶体进行破坏。TRIM21特别适用于这一目的，因为其“RING”部分只有在两个或两个以上的TRIM21蛋白质聚集在一起时才会被激活。这意味着，只有当TRIM21蛋白与相邻的tau蛋白聚集物结合时，它才会激活并标记其靶标用于随后的破坏。新的特洛伊木马疗法在这两篇论文中，研究者利用TRIM21创造了两种针对tau聚集物的新疗法。第一种疗法是“RING-纳米抗体（RING-nanobody）”，它将结合tau蛋白的纳米抗体与TRIM21 RING结合在一起。第二种疗法是“RING-诱饵（RING-Bait）”，它将TRIM21 RING与tau蛋白本身的一个拷贝连接在一起。与TRIM21 RING连接的tau蛋白像诱饵一样，tau蛋白聚集物会将其纳入其中，TRIM21 RING也会被纳入其中。一旦在tau蛋白聚集物中加入多个RING-Bait，它们就会被激活，导致整个聚集物被破坏。研究者将编码这两种TRIM21疗法的DNA递送到含有tau聚集物的细胞中，发现这能清除tau缠结，而“健康”的tau蛋白没有被破坏。剑桥大学英国痴呆症研究所的Will McEwan博士说：“tau聚集物藏在脑细胞内，很难降解。重要的是，这些基于TRIM21的新疗法可以直接在细胞内施用，大部分tau聚集物就在细胞内。我们找到不仅能降解tau聚集物还能让健康的tau完好无损地发挥作用的方法。这种新策略超越了目前正在进行临床试验的反义寡核苷酸疗法，因为它可以避免消除正常tau可能产生的任何长期副作用。” 临床前研究结果研究者在由阿尔茨海默病或进行性核上性麻痹患者捐献的脑组织中含有tau蛋白聚集物的细胞上测试了这两种疗法。结果显示，RING-Bait疗法能够防止来自阿尔茨海默病和进行性核上性麻痹患者大脑中的蛋白诱导的tau聚集。MRC分子生物学实验室的Leo James博士说：“神经退行性疾病的tau蛋白会以多种不同的方式发生错误折叠，因此每种疾病都可能需要不同的治疗方法。RING-Bait的一个有用之处在于，因为它附着在tau蛋白上，所以它是一个通用的特洛伊木马，应该像细胞自身错误折叠的tau蛋白一样，被整合到不同类型的tau聚集物中。” 小鼠实验结果——运动功能明显改善为了使这种治疗在动物体内发挥作用，研究者使用了一种无害的病毒，即腺相关病毒（AAV），递送DNA指令，在脑细胞内制造定制的蛋白质。对携带tau蛋白聚集物的老年小鼠注射单剂量的AAV载体，几周内，接受治疗的动物脑细胞中聚集的tau数量明显减少。重要的是，接受RING-Bait治疗的小鼠的神经退行性症状进展减缓，运动功能明显改善，这是由人工智能程序对小鼠的奔跑能力进行评估得出的结果。 Lauren Miller博士说：“我们之前并不知道专门清除细胞内的tau聚集物是否足以阻止疾病的进展。令人鼓舞的是，在我们的模型系统中，RING-Bait方法降低了疾病的严重程度，这表明选择性清除tau聚集物是一种有效的治疗方法。还需要进一步的研究来证明这种有益效果在多种人类疾病模型中都能实现。” 未来展望 MRC分子生物学实验室的Guido Papa博士说：“RING-Bait的优点在于它具有广泛的适应性，并有可能解决以病理蛋白簇积累为特征的其他疾病。其他神经退行性疾病是由其他蛋白形成的聚集物引起的，如运动神经元疾病中的TDP43和帕金森病中的α-突触核蛋白。我们希望，RING-Bait未来能够开发出直接针对这些疾病聚集过程的疗法。” 研究者告诫说，这些疗法在开展人体临床试验之前仍需要大量的开发工作，尤其是开发一种AAV载体，能够安全有效地将RING-nanobody或RING-bait疗法递送到整个人脑的细胞中。剑桥大学英国痴呆症研究所的Jonathan Benn博士说：“尽管我们在小鼠模型中证明了它的有效性，但这离可用于人类的疗法还有很长的路要走。我们需要确定在人脑中使用基于TRIM21的疗法是否安全，以及这类疗法是否能有效清除聚集物和改善病程。一些AAV载体已被批准用于人类，如退行性眼病和脊髓性肌肉萎缩症等遗传疾病。然而，要将足够的AAV植入成人大脑仍是一项重大挑战，人脑比小鼠大脑大1000倍。但这是一个快速发展的领域，我们希望未来能有最先进的基因递送方法来大规模递送我们的疗法。” 参考资料： Lauren V.C. Miller et al. Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function. Cell, 2024, doi:10.1016/j.cell.2024.08.024. Jonathan Benn et al. Aggregate-selective removal of pathological tau by clustering-activated degraders. Science, 2024, doi:10.1126/science.adp5186. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

临床1期信使RNA临床结果临床终止寡核苷酸

2023-02-16

·PRNewswire

DelveInsight Evaluates a Robust Prostate Cancer Pipeline as 170+ Influential Pharma Players to Set Foot in the Domain

Prostate cancer is the most common cancer in men and accounts for the second most cancer deaths among men globally. The rise in the number of cases of prostate cancer has led to growing government funding and rising initiatives by public and private organizations to spread awareness about prostate cancer. The emergence of strong pipeline drugs and the presence of novel prostate cancer treatments are the prominent factors that will escalate the growth rate of the prostate cancer therapeutics market. LAS VEGAS, Feb. 16, 2023 /PRNewswire/ -- DelveInsight's ' Prostate Cancer Pipeline Insight – 2023 ' report provides comprehensive global coverage of available, marketed, and pipeline prostate cancer therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the prostate cancer pipeline domain. Key Takeaways from the Prostate Cancer Pipeline Report DelveInsight's prostate cancer pipeline report depicts a robust space with 170+ active players working to develop 200+ pipeline therapies for prostate cancer treatment. Key prostate cancer companies such as Merck & Co, Pfizer, Orion, Zenith Epigenetics, ESSA Pharma, RhoVac, AstraZeneca, Advaxis, Inc., Tracon Pharmaceuticals Inc., Bristol-Myers Squibb, Laekna Limited, Bracco Diagnostics, Inc, Arvinas Inc, Epizyme, Regeneron Pharmaceuticals, Veru Inc., Eli Lilly and Company, Exelixis, Luye Pharma Group, Amgen, Innocrin Pharmaceutical, Bayer, Nymox Pharmaceutical, Matrix Biomed, Tavanta Therapeutics, Fortis Therapeutics, Inc., Janssen Research & Development, LLC, Clarity Pharmaceuticals, Leap Therapeutics, Hinova pharmaceuticals, Vaccitech, Cardiff Oncology, Suzhou Kintor Pharmaceuticals, Teneobio, Inc., Janux Therapeutics, Fusion Pharmaceuticals, Corbus Pharmaceuticals, BioXcel Therapeutics, Onxeo S.A, Ayala Pharmaceuticals, HOOKIPA Pharma, Nuvation Bio, Ambrx, enGene, Jemincare, CellVax Therapeutics, POINT Biopharma, Oncternal Therapeutics, Immunic AG, BioNTech SE, and others are evaluating new prostate cancer drugs to improve the treatment landscape. Promising prostate cancer pipeline therapies in various stages of development include Pembrolizumab, Talazoparib, ODM-208, ZEN 3694, EPI-7386, RV 001, Adavosertib, Capivasertib, ADXS31-142, TRC253, Nivolumab, LAE001, BR55, ARV-110, Tazemetostat, REGN5678, VERU-111, Abemaciclib, Cabozantinib, LY01005, Tarlatamab, VT-464, BAY2315497, NX-1207, MBM-02, TAVT-45, FOR46, JNJ-78278343, 64Cu-SAR-bisPSMA, DKN-01, HC-1119, ChAdOx1-MVA 5T4, Onvansertib, GT0918, TNB-585, JANX007, 225Ac-PSMA I&T, CRB-701, BXCL701, AsiDNA, ADXS-504, HB-300, NUV-868, ARX517, JMKX002992, Zilovertamab, IMU-935, BNT112, and others. In February 2023, Fusion Pharmaceuticals announced the acquisition from RadioMedix, Inc. of the investigational new drug application for an ongoing Phase II clinical trial (the "TATCIST" trial) evaluating 225Ac-PSMA I&T, a small molecule targeting prostate-specific membrane antigen ("PSMA") expressed on prostate cancers. Following the closing, the alpha-emitting radiopharmaceutical being evaluated in the TATCIST trial will be known as FPI-2265. In February 2023, Corbus Pharmaceuticals entered into an exclusive licensing agreement with CSPC Megalith Biopharmaceutical Co., Ltd, a subsidiary of CSPC Pharmaceutical Group Limited for development and commercialization of CRB-701 (SYS6002): a novel clinical-stage antibody drug conjugate (ADC) targeting Nectin-4. The agreement covers exclusive commercialization rights to CRB-701 in the United States, Canada, the European Union (including the European Free Trade Area), the United Kingdom, and Australia. CSPC will retain all rights to SYS6002 in the remaining global markets. Clinical development is underway and will focus on urothelial cancer and other Nectin-4-positive solid tumors, potentially including lung, breast and prostate cancer. In February 2023, BioXcel Therapeutics, Inc.reported full data from its Phase IIa trial of BXCL701, the Company's investigational, oral innate immune activator, in combination with KEYTRUDA (pembrolizumab) in small cell neuroendocrine (SCNC) variant metastatic castration-resistant prostate cancer (mCRPC) patients after at least one prior line of chemotherapy for locally advanced or metastatic prostate cancer. Results will be presented in a rapid abstract presentation and a poster presentation at the 2023 American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium on February 16, 2023. In January 2023, Onxeo S.A. gave an update on the clinical development program of its first-in-class drug candidate AsiDNA. Onxeo has activated its first US clinical study site, Next Oncology San Antonio. This phase I/II multicenter, basket trial intends to assess the safety and preliminary activity of AsiDNA in combination with olaparib in patients with recurrent ovarian, breast, and metastatic castration-resistant prostate cancer (mCRPC) who have progressed on previous PARP inhibitor therapy. In October 2022, Ayala Pharmaceuticals, Inc. and Advaxis, Inc. entered into a definitive merger agreement. The merger would result in a combined company that will focus predominantly on the development and commercialization of Ayala's lead program AL102 for the treatment of desmoid tumors and Advaxis's candidate ADXS-504 in development for prostate cancer. In October 2022, Janux Therapeutics announced that the first patient had been dosed in Phase I clinical trial of JANX007 in subjects with metastatic castration-resistant prostate cancer (mCRPC). JANX007 is a prostate-specific membrane antigen (PSMA) directed T cell engager (TCE) and is the first product candidate utilizing Janux's TRACTr platform to be administered in humans. Request a sample and discover the recent advances in prostate cancer drug treatment @ Prostate Cancer Pipeline Report The prostate cancer pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage prostate cancer drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the prostate cancer clinical trial landscape. Prostate Cancer Overview Prostate cancer is a type of cancer that arises from the prostate gland. It is the second leading cause of cancer death in men in the United States. 1 in every 9 men will be diagnosed with prostate cancer during their lifetime. Prostate cancer will be diagnosed in nearly 250,000 men this year. Breaking away from a prostate tumor allows prostate cancer cells to spread. They can spread to other body parts by passing through blood vessels or lymph nodes. Cancer cells that have spread may attach to other tissues and grow to form new tumors, causing damage wherever they land. Prostate cancer symptoms vary from person to person. Some men have no symptoms at all. Common prostate cancer symptoms include blood in the urine or semen, painful ejaculation, pain or burning during urination, and others. A biopsy is a primary tool for prostate cancer diagnosis, but a doctor can use other tools to ensure that the biopsy is performed in the correct location. Doctors may, for example, use transrectal ultrasound or magnetic resonance imaging (MRI) to guide the biopsy. Find out more about drugs for prostate cancer @ New Prostate Cancer Drugs A snapshot of the Prostate Cancer Pipeline Drugs mentioned in the report: Learn more about the emerging prostate cancer pipeline therapies @ Prostate Cancer Clinical Trials Prostate Cancer Therapeutics Assessment The prostate cancer pipeline report proffers an integral view of prostate cancer emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Prostate Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Parenteral, Intravenous, Subcutaneous, Topical Therapeutics Assessment By Molecule Type: Monoclonal Antibody, Peptides, Polymer, Small molecule, Gene therapy Therapeutics Assessment By Mechanism of Action: Programmed cell death-1 receptor antagonists, Poly(ADP-ribose) polymerase inhibitors, Proto oncogene protein c-akt inhibitors, Tubulin inhibitors; Tubulin polymerisation inhibitors, Antioxidants; Blood coagulation factor inhibitors; Inflammation mediator inhibitors; RNA replicase inhibitors, Bromodomain and extraterminal domain protein inhibitors, Immunostimulants, DNA topoisomerase I inhibitors, Androgen receptor antagonists, Polycomb repressive complex 2 inhibitors Key Companies: Merck & Co, Pfizer, Orion, Zenith Epigenetics, ESSA Pharma, RhoVac, AstraZeneca, Advaxis, Inc., Tracon Pharmaceuticals Inc., Bristol-Myers Squibb, Laekna Limited, Bracco Diagnostics, Inc, Arvinas Inc, Epizyme, Regeneron Pharmaceuticals, Veru Inc., Eli Lilly and Company, Exelixis, Luye Pharma Group, Amgen, Innocrin Pharmaceutical, Bayer, Nymox Pharmaceutical, Matrix Biomed, Tavanta Therapeutics, Fortis Therapeutics, Inc., Janssen Research & Development, LLC, Clarity Pharmaceuticals, Leap Therapeutics, Hinova pharmaceuticals, Vaccitech, Cardiff Oncology, Suzhou Kintor Pharmaceuticals, Teneobio, Inc., Janux Therapeutics, Fusion Pharmaceuticals, Corbus Pharmaceuticals, BioXcel Therapeutics, Onxeo S.A, Ayala Pharmaceuticals, HOOKIPA Pharma, Nuvation Bio, Ambrx, enGene, Jemincare, CellVax Therapeutics, POINT Biopharma, Oncternal Therapeutics, Immunic AG, BioNTech SE, and others. Key Prostate Cancer Pipeline Therapies: Pembrolizumab, Talazoparib, ODM-208, ZEN 3694, EPI-7386, RV 001, Adavosertib, Capivasertib, ADXS31-142, TRC253, Nivolumab, LAE001, BR55, ARV-110, Tazemetostat, REGN5678, VERU-111, Abemaciclib, Cabozantinib, LY01005, Tarlatamab, VT-464, BAY2315497, NX-1207, MBM-02, TAVT-45, FOR46, JNJ-78278343, 64Cu-SAR-bisPSMA, DKN-01, HC-1119, ChAdOx1-MVA 5T4, Onvansertib, GT0918, TNB-585, JANX007, 225Ac-PSMA I&T, CRB-701, BXCL701, AsiDNA, ADXS-504, HB-300, NUV-868, ARX517, JMKX002992, Zilovertamab, IMU-935, BNT112, and others. Dive deep into rich insights for new drugs for prostate cancer treatment; visit @ Prostate Cancer Medications Table of Contents For further information on the prostate cancer pipeline therapeutics, reach out @ Prostate Cancer Drug Treatment Related Reports Metastatic Prostate Cancer Pipeline Metastatic Prostate Cancer Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products and the key metastatic prostate cancer companies, including Veru, Tracon, Sotio, among others. Metastatic Castration-Sensitive Prostate Cancer Pipeline Metastatic Castration-Sensitive Prostate Cancer Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key metastatic castration-sensitive prostate cancer companies, including Merck, Pfizer, Veru, Tracon, Sotio, among others. Metastatic Hormone-Refractory Prostate Cancer Pipeline Metastatic Hormone-Refractory Prostate Cancer Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key metastatic hormone-refractory prostate cancer companies, including Merck, Pfizer, Veru, Tracon, Sotio, among others. Metastatic Castration-Resistant Prostate Cancer Epidemiology Forecast Metastatic Castration-Resistant Prostate Cancer Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology as well as the metastatic castration-resistant prostate cancer epidemiology trends. Metastatic Castration-Resistant Prostate Cancer Market Metastatic Castration-Resistant Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key metastatic castration-resistant prostate cancer companies including Zenith Epigenetics, Surface Oncology, Opna-IO LLC, Regeneron Pharmaceuticals, Veru Inc, among others. Other Trending Reports Tay-sachs Disease Or Gm2 Gangliosidosis Market | Onycholysis Market | Diagnostic Imaging Equipment Market | Chemotherapy-induced Peripheral Neuropathy Market | Global Electrophysiology Devices Market | Anaphylaxis Market | Atherectomy Devices Market | Helicobacter Pylori Infections Market | Ophthalmic Imaging Equipment Market | Androgenetic Alopecia Market | Allergic Rhinitis Market | Chronic Inflammatory Demyelinating Polyneuropathy Market | Chronic Inflammtory Demyelinating Polyneuropathy Market | Colorectal Cancer Crc Market | Opioid Induced Constipation Market | Vertigo Market | Bone Anchored Hearing Systems Market | Wound Closure Devices Market | Hip Replacement Devices Market | Hemodynamic Monitoring Systems Market | Egfr Non-small Cell Lung Cancer Market | Helicobacter Pylori Infection Market | Hyperkalemia Market | Polycythemia Market Neurostimulation Devices Market | Carpal Tunnel Syndrome Market | Ventilator Market | Cerebral Aneurysm Market | Alpha Antitrypsin Market | Binge Eating Disorder Market | Bunion Market | Concussions Market Size | Exocrine Pancreatic Insufficiency Market | Healthcare Due Diligence Services | Minimal Residual Disease Market | Hypertrophic Scar Market | Lung Fibrosis Market | Anterior Uveitis Market | 22q11.2 deletion syndrome Market | X-Linked Retinitis Pigmentosa (XLRP) Market | Acute Radiation Syndrome Market | Alpha-1 Protease Inhibitor Deficiency Market | Androgenetic Alopecia Market | Hyperlipidemia Market | Cardiotoxicity Market | Hypertrophic Cardiomyopathy Market | Fatty Acid Oxidation Disorders (FAODs) Market | Androgen Insensitivity Syndrome Market | Emphysema Market | Canaloplasty Market | Dravet Syndrome Market | Celiac Disease Market | Chlamydia Infections Market | Syphilis Market | Renal Tubular Acidosis Market | Palmoplantar Pustulosis (PPP) Market | Aplastic Anemia Market | Bacterial Pneumonia Market | B cell Chronic Lymphocytic Leukemia Market | B cell Lymphomas Market | Behcets Disease Market Neoantigen-based Personalized Cancer therapeutic Vaccines Competitive Landscape and Market Forecast—by 2035 | Glioblastoma Market Related Healthcare Blogs Metastatic Castration-Sensitive Prostate Cancer Market PARP Inhibitors for Metastatic Castration-Resistant Prostate Cancer Prostate Cancer Market Outlook Related Healthcare Services Healthcare Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Connect with us on LinkedIn |Facebook|Twitter Additionally, get in touch with our business executive to explore @ Healthcare Due Diligence Services Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

临床1期临床2期ASCO会议

2022-07-26

·生物制药小编

基因编辑治疗时代已来：三大基因编辑治疗策略

近日，基因编辑技术迎来了重要里程碑。Verve Therapeutics 公司宣布，其开发的碱基编辑疗法 VERVE-101 在新西兰获批开展人体临床试验，用于治疗杂合子家族性高胆固醇血症（HeFH），这也是首个体内碱基编辑的临床试验。目前已有几种类型的基因编辑剂已被用于体内基因编辑治疗，本文就常用的三大基因编辑治疗策略做一个简单介绍(图1)。图1. 治疗性基因编辑三大策略核酸酶目前，基本上在哺乳动物细胞中进行基因编辑都涉及到使用核酸酶，其在基因组DNA的特定位置产生双链断裂(DSB)。归巢核酸内切酶(Meganuclease)、锌指核酸酶(ZFN)和转录激活物样效应核酸酶(TALEN)是第一批用于哺乳动物细胞基因编辑的酶（图2）。然而，由于这些编辑剂在切割前依赖复杂的蛋白质：DNA相互作用来结合特定的DNA序列，因此必须在新的基因组目标位置设计和构建新的编辑蛋白质。这些方法是非常耗时、耗力的。图2. 用于基因编辑的核酸酶发展时间线CRISPR-Cas核酸酶使基因编辑发生了革命性的变化，因为这些酶可以通过Cas蛋白中装载的简单single-guide RNA (sgRNA)识别目标DNA分子进行基因编辑。这使得研究人员能够对 CRISPR-Cas 核酸酶进行编程，以仅通过改变 sgRNA 的 20 个碱基对部分的序列来靶向和切割不同的基因组位点，而无需设计新的 Cas 蛋白。目前，CRISPR-Cas 核酸酶是迄今为止用于在哺乳动物细胞中产生靶向 DSB 最广泛使用的酶。在哺乳动物细胞中，DSB最常见的修复方式是非同源末端连接或微同源介导的末端连接，这两种方法都会导致靶点上插入和缺失的不可控分布。在某些情况下，DSB可以通过同源定向修复。这一过程可以由外源DNA供体作为模板，该供体可以包含任何任意序列，两侧是与靶点同源的区域，原则上可以用于在基因组DNA中安装任何所需的序列。然而，同源定向修复在大多数细胞类型中都是低效的，包括非分裂细胞，并且成功的同源定向修复编辑结果通常伴随着大量的插入或缺失改变。出于这些原因，对于将突变的基因精确地纠正为正确的序列，并最大限度地减少不需要的编辑副产品，核酸酶介导的基因编辑通常是一种很差的通用策略。然而，核酸酶通过引入移码突变来扰乱基因的编码序列，或者破坏非编码序列中的调控基序来调节基因的表达是十分有效的。在用核酸酶进行的基因编辑中，目前绝大多数治疗方式是破坏目标基因组位点。尽管可编程核酸酶已经被应用于治疗，但也有报道称，核酸酶介导的基因编辑会产生一些不良后果。除了靶点的插入或缺失外，在基因组DNA中产生DSB还会导致大的缺失、染色体易位等。这些缺点，促使了更精确的基因编辑替代策略的发展。碱基编辑碱基编辑克服了核酸酶的许多限制，通过基因组DNA中的单核苷酸转换实现了精确的基因校正，而不需要DSB。碱基编辑是由融合到可编程DNA结合域的DNA修饰酶组成的。迄今已有许多不同类型的碱基编辑被报道。最早报道的碱基编辑是胞嘧啶碱基编辑分子，它执行靶向的C·G向T·A的转换，由胞苷脱氨酶融合到催化受损的Cas酶和尿嘧啶糖基酶抑制物(UGIs)组成。在典型的胞嘧啶碱基编辑中，催化受损的Cas酶首先与特定的基因组位点结合，而不产生DSB。引导RNA和靶DNA链之间的碱基配对暴露出单链DNA bubble，该bubble可被融合的胞苷脱氨酶结构域进行脱氨基。由于融合的胞苷脱氨酶是单链DNA底物所特有的，脱氨作用被限制在暴露的DNA链内的一个小窗口内。胞嘧啶的脱氨基产生尿嘧啶，它被融合的UGIs部分保护而不被切除，导致目标DNA位点上的U·G错配。催化受损的Cas酶选择性地只切割未编辑的含有G的链而不产生DSB，这会偏向细胞错配修复。由此产生的 U·A 碱基对最终通过细胞修复机制转化为 T·A 碱基对。如果含尿嘧啶的中间体没有受到保护，而是促进了尿嘧啶的切除，结果通常是 C·G向G·C 转化，而不是 C·G向T·A 转化。这一现象被用来设计基于C·G到G·C的编辑程序。腺嘌呤碱基编辑通过类似的机制执行A·T到G·C转换。由于目前还没有已知的天然酶催化脱氧腺苷进行脱氨基，迄今为止描述的所有腺嘌呤碱基编辑都是使用实验室进化的脱氧腺苷脱氨酶。腺嘌呤碱基编辑是一类特别有用的碱基编辑程序，因为它们逆转了最常见的致病点突变类型(C·G 向T·A)，这种突变约占已知致病单核苷酸多态(SNPs)的一半.自从最初的胞嘧啶碱基编辑和腺嘌呤碱基编辑的开发以来，许多实验室已经报告了数百个不同性质的碱基编辑。碱基编辑已被用于应用各种体外和体内编辑治疗，以纠正致病点突变或或插入可预防或挽救疾病表型的单核苷酸变体。先导编辑（Prime editors）虽然碱基编辑原则上可以纠正大多数致病SNPs，但它们不能执行所有可能的单核苷酸转换，也不能介导靶向插入或缺失。为了解决这些限制，研究人员开发了先导编辑器，它允许编程安装任何单核苷酸转换、小的插入、删除或其组合，而不会产生DSB。先导编辑器由一个融合到Cas9切口酶结构域的逆转录酶组成，并使用一个经过工程化的先导编辑引导 RNA（pegRNA）来将Cas9切口酶定向到特定的靶点，进而对感兴趣的碱基进行编辑。先导编辑器首先切割非靶标DNA链，并使用产生的自由3’端以pegRNA延伸为模板启动逆转录。在将所需的编辑加入到新合成的链之后，可以使用额外的缺口来引导DNA修复，以通过使用编辑的链作为模板来替换未编辑的链。已经有些研究报道了使用先导编辑器在体内进行编辑的例子。最近对先导编辑器和 pegRNA 的改进已实现了对各种细胞类型的高效编辑。这将对未来的体内编辑发挥巨大作用。小编小结全世界有数百万人患有遗传疾病，原则上其可以通过治疗性DNA编辑试剂来纠正。CRISPR-Cas技术的广泛发展和优化已经产生了强大的基因编辑工具，包括可编程核酸酶、碱基编辑和先导编辑。将这些基因编辑工具与高效的递送方法相结合已经产生了强大的治疗结果。新的体内基因编辑疗法正迅速走向临床，人类活体基因编辑治疗的时代已经到来。参考文献Therapeutic in vivo delivery of gene editing agents.Genome Editing B.C. (Before CRISPR): Lasting Lessons from the ‘‘Old Testament’’.In Vivo Delivery Systems for Therapeutic Genome Editing.

基因疗法

100 项与 Etidaligide 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床2期	美国	Valerio Therapeutics SA	2023-02-20
转移性去势抵抗性前列腺癌	临床2期	美国	Valerio Therapeutics SA	2023-02-20
卵巢上皮癌	临床2期	美国	Valerio Therapeutics SA	2023-02-20
胶质瘤	临床2期	欧洲	-	2021-04-19
卵巢癌	临床2期	法国	-	2020-09-08
黑色素瘤	临床2期	-	Valerio Therapeutics SA	-
晚期癌症	药物发现	比利时	Valerio Therapeutics SA	2018-04-05
晚期恶性实体瘤	药物发现	法国	Valerio Therapeutics SA	2018-04-05
晚期恶性实体瘤	药物发现	比利时	Valerio Therapeutics SA	2018-04-05
转移性黑色素瘤	药物发现	法国	DNA Therapeutics SASU	2011-10-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


EUCTR2020-000825-18-FR (RevoCAN, ESMO2023) 人工标引	临床1/2期	卵巢癌	12	AsiDNA™ 600 mg + PARPi (dose de-escalation part)	(構淵願鬱窪憲遞窪鑰廠) = 廠衊廠艱鹹廠遞窪鬱範憲簾獵鹹鬱淵鏇衊糧膚 (糧艱窪鹹壓願蓋夢齋鑰 )	积极	2023-10-22
EUCTR2020-000825-18-FR (RevoCAN, ESMO2023) 人工标引	临床1/2期	卵巢癌	12	AsiDNA™ 600 mg + PARPi	(觸壓鹽淵鹽艱醖鑰願鹽) = 廠夢鏇鏇簾鹹構製鹽壓糧觸襯鏇鏇觸積憲顧簾 (衊壓廠範鬱願餘壓窪廠 ) 更多	积极	2023-10-22
NCT03579628 (DRIIV-1, Pubmed \| Med J Aust) 人工标引	临床1期	晚期恶性实体瘤	22	AsiDNA	(糧願鹹壓襯構鏇範衊築) = 壓齋構鏇獵淵鬱顧鹹醖顧淵鹹艱襯蓋壓艱網積 (觸壓艱鑰選壓網觸鑰醖 ) 更多	积极	2020-11-01
NCT01469455 (Pubmed \| Med J Aust) 人工标引	临床1期	黑色素瘤	23	Radiotherapy+DT01	(鹹選顧獵醖蓋簾鹹糧築) = injection site reactions 鑰顧範衊鏇網衊簾顧鹽 (築選獵淵膚艱蓋觸醖築 ) 更多	积极	2016-05-24
NCT01469455 (ASCO2015)	临床1期	黑色素瘤	27	DT01 + Radiotherapy	(積鏇憲艱餘製鹹獵廠築) = 構醖齋獵窪鏇顧壓醖網醖糧遞遞獵餘獵醖鏇艱 (獵構艱獵鹽餘壓鑰鑰顧 )	-	2015-05-20
NCT01469455 (ASCO2015)	临床1期	黑色素瘤	27	Radiotherapy	(積鏇憲艱餘製鹹獵廠築) = 憲製網鹹觸襯鑰艱餘蓋醖糧遞遞獵餘獵醖鏇艱 (獵構艱獵鹽餘壓鑰鑰顧 )	-	2015-05-20