NOS2

Primary CoQ10 deficiency is a rare mitochondrial disorder that impacts fewer than one in 100,000 individuals. Credit: StudioMolekuul via Shutterstock. BPGbio has received a Rare Pediatric Disease Designation from the US Food and Drug Administration (FDA) for BPM31510IV to treat primary coenzyme Q10 deficiency, an ultra-rare mitochondrial disorder. Primary CoQ10 deficiency affects fewer than one in 100,000 people. It hampers the body’s ability to produce CoQ10, a molecule crucial for cellular energy production and biomembrane stabilisation. The deficiency can lead to severe developmental delays, weakness of muscle, seizures, and potentially fatal organ damage, with symptoms often appearing in early childhood. Oral CoQ10 supplements failed to reach therapeutic levels in severely affected organs. BPGbio’s BPM31510IV has shown potential in addressing this gap, leveraging the company’s NAi Interrogative Biology platform, which combines patient biology with AI-driven analysis. See Also: Potential for peptides to replace antibodies in radiopharma, says WuXi AppTec exec BPGbio’s mitochondrial disorder drug gets paediatric disease status It is not only a lead candidate for solid tumours such as glioblastoma multiforme and pancreatic cancer but also shows promise for various rare diseases. BPGbio president and CEO Niven Narain said: “BPM31510 has been developed in topical, IV and oral formulations and is a prime example of the power of our biology-first approach to drug discovery and development, illustrating the powerful predictive capabilities of our NAi Interrogative Biology platform, and the benefit of validating AI-derived predictions through wet lab experiments and in vivo modelling. “By using hypothesis-free causal AI to analyse vast amounts of biological data, we were able to uncover and validate new potential applications BPM31510, including its potential to address mitochondrial diseases like primary CoQ10 deficiency.” BPGbio’s investigational treatment has also received orphan drug designation for glioblastoma multiforme, pancreatic cancer, and epidermolysis bullosa, in addition to the rare pediatric disease designation for primary CoQ10 deficiency.

*仅供医学专业人士阅读参考最近奇点糕给各位唠的癌症相关研究里，有不少都在拷打人体内沦为癌细胞帮凶的细胞，像成纤维细胞和巨噬细胞就被批过不止一次了，但奇点糕掐指一算，好像很久没看到关注肿瘤微环境内中性粒细胞的研究了？总不会是它们真就改邪归正了吧？可惜啊，江山易改本性难移。近日，复旦大学附属华山医院陆录、钦伦秀、朱文伟牵头在Journal for ImmunoTherapy of Cancer期刊发表的研究成果，又一次实锤了中性粒细胞在肝细胞癌（HCC）免疫抑制性微环境中的“黑手”角色，并借助CRISPR筛选技术，找到了介导中性粒细胞抑制T细胞免疫功能的关键靶点——糖原合酶激酶3α（GSK3A）。该研究揭示，GSK3A可通过NF-κB/STAT3信号轴影响HCC细胞的亮氨酸丰富α2-糖蛋白1（LRG1）分泌水平，LRG1则会促进中性粒细胞的自我趋化（self-chemotaxis），并介导中性粒细胞陷阱（NETs）的形成，由此导致T细胞的细胞毒性功能受到显著抑制；而在实验中将GSK3A抑制剂与PD-1抑制剂联合使用，有望助力HCC免疫治疗打破疗效瓶颈[1]。论文首页截图与既往研究“直扑”HCC微环境内中性粒细胞的做法不同，华山医院团队此次的研究始于CRISPR筛选，具体方法是将涵盖近2800个免疫相关基因的单向导RNA（sgRNA）文库转染到HCC细胞内，然后将HCC细胞分别植入免疫健全和免疫缺陷小鼠体内，如果某个基因仅能在免疫健全小鼠体内显著加速HCC肿瘤生长，那就是免疫抑制相关的候选基因。在将初步筛选结果与人类转录组学和蛋白质表达水平对照后，研究者们确定了含Gsk3a在内的5个候选基因，又在HCC模型小鼠（免疫健全）身上将它们逐个分别敲除，而敲除Gsk3a的抑癌效应最为显著，它就成了下一步研究的主要对象，不过初步试验也显示，敲除Gsk3a或使其过表达，并不会直接影响HCC细胞的增殖、迁移、凋亡等关键属性。影响肿瘤生长但又不直接作用于癌细胞，那机制一定与免疫微环境有关了。研究者们比对了敲除HCC细胞Gsk3a前后肿瘤微环境的免疫细胞变化，发现仅有中性粒细胞（Gr+Ly6g+）显著减少，而其它免疫细胞数量基本不变，但效应T细胞（IFN-γ+/GZMB+ CD8+）的占比明显上升，而耗竭T细胞相应减少，显然Gsk3a、中性粒细胞和T细胞三者当中“有瓜”。敲除Gsk3a会影响HCC微环境内的中性粒细胞数量和T细胞免疫功能体外共培养实验显示，是否敲除HCC细胞的Gsk3a，都不会使它们直接影响T细胞功能，但加入中性粒细胞后，Gsk3a未被敲除的HCC细胞就能抵御T细胞杀伤，且Gsk3a也会直接影响HCC细胞募集中性粒细胞的能力；而与Gsk3a未被敲除的HCC细胞共培养时，中性粒细胞内表达变化最显著的基因，也主要与趋化作用相关（如趋化因子Cxcl1/2/3）。从整体上看，这些中性粒细胞的表型并不像肿瘤相关中性粒细胞普遍会分出的N1/N2表型[2]，然而研究者们敏锐地捕捉到，与NETs形成有关的Nos2基因表达也有上调，而Gsk3a水平的变化（敲除或过表达）也对应着HCC微环境内NETs的数量改变，特别是在Gsk3a过表达时，增多的NETs就会成为HCC细胞的保护罩，将细胞毒性CD8+T细胞隔绝在外，甚至NETs还会通过上调PD-L1表达，再加一道免疫抑制的保险，使T细胞望癌兴叹。GSK3A的存在会导致中性粒细胞形成更多NETs，保护癌细胞不被T细胞杀伤最后，研究者们明确了癌细胞GSK3A调控中性粒细胞形成NETs的具体机制：GSK3A会经由NF-κB/STAT3信号轴诱导HCC细胞分泌LRG1，而既往研究已经揭示，LRG1能通过自分泌效应，诱导并放大中性粒细胞的自我趋化[3]，促进NETs形成来抑制T细胞功能，本次研究也再度证实了相关发现。初步细胞实验也证实，已有的GSK3A抑制剂（SB216763）能够与PD-1抑制剂协同增效，增敏HCC免疫治疗的潜在方案又喜+1啦一图总结论文核心内容------奇点糕近期推出了《2024ASCO年会深度盘点》课程，为大家系统盘点了2024ASCO年会上实体瘤领域的重磅进展，让您在100分钟内迅速深入把握前沿。长按识别下图中的二维码即可购买，购买后您可以在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。如果遇到任何技术问题，大家可以戳我们下图中的客服小伙伴来解决~~参考文献：[1]Zheng X, Yang L, Shen X, et al. Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma[J]. Journal for ImmunoTherapy of Cancer, 2024, 12(8): e009642.[2]Masucci M T, Minopoli M, Carriero M V. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy[J]. Frontiers in Oncology, 2019, 9: 1146.[3]Yu B, Yang L, Song S, et al. LRG1 facilitates corneal fibrotic response by inducing neutrophil chemotaxis via Stat3 signaling in alkali-burned mouse corneas[J]. American Journal of Physiology-Cell Physiology, 2021, 321(3): C415-C428.本文作者丨谭硕

SAN FRANCISCO--( BUSINESS WIRE )-- BIOMAKERS , a Precision Medicine & Biotech Company that supports data-driven Drug Development globally, and TOPAZIUM , an AI-driven healthtech company specializing in drug discovery and human wellbeing, have announced the results of their innovative collaborative project. This partnership showcases the power of AI systems in leveraging real-world DNA sequencing data to identify novel targets aimed at improving the efficacy of immunotherapy for non-small cell lung cancer (NSCLC) treatment. The findings were presented at the prestigious 2024 American Society of Clinical Oncology (ASCO) meeting in Chicago. The study used Whole Exome Sequencing (WES) data from biopsies of squamous and adenocarcinoma NSCLC processed through BIOMAKERS ' advanced DNA sequencing platforms. The data was then analyzed using GFPrint™, a proprietary algorithm developed by TOPAZIUM , that generates virtual representations of tumor exomes in a latent space defined by the genetic features of the samples. “The advent of drugs targeting the PD-1/PD-L1 axis has revolutionized NSCLC treatment. Although promising, individual responses to these therapies can vary, and we believe this ongoing project will help to better understand mechanisms involved in PD1/PD-L1 expression, optimize treatment protocols, and identify which patients are most likely to benefit from these therapies. In this study, DNA sequencing and GFPrint™ were employed to identify mutations in genes linked to PD-L1 expression in NSCLC adenocarcinoma tumor samples,” said Dr. Rubén Salanova, Chief Medical Officer & Co-Founder of BIOMAKERS . “Using this strategy, we have identified a subpopulation of adenocarcinoma patients with increased PD-L1 expression levels, enriched in non-silent mutations of 10 genes of interest, mostly included in the HIF-1α signaling pathway. Notably, 6 of these mutated genes (PIK3R1, HK1, NOS2, NRAS, BRAF, ITGA1) were uniquely found in adenocarcinomas” said Juan Manuel Domínguez, Head of Preclinical & Biostatistics at TOPAZIUM . “All these newly identified genes deserve further studies to validate them as potential targets for pharmacological intervention concomitant with PD-1/PD-L1 blockade, and as potential biomarkers for patient selection to improve the efficiency of immunotherapy in NSCLC treatment,” added Andrea Mendoza, Head of R&D at BIOMAKERS . For more details, the abstract can be accessed at: https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13600 For more information about GFPrint™, visit: https://www.biorxiv.org/content/10.1101/2024.03.08.584090v4 About BIOMAKERS: BIOMAKERS is an Oncology Precision Medicine Company with a Comprehensive Genomic Platform and reach throughout LATAM, delivering care-changing solutions. In addition to its strong focus on physician support and patient care, their Life Science division partners with biopharma companies to advance R&D programs by providing support for Drug Discovery and Drug Development. This innovative work is enabled by direct partnerships with renowned Health Institutions across 17 different countries. contacto@biomakers.net About TOPAZIUM: TOPAZIUM is committed to supporting medical research with artificial intelligence (AI) through state-of-the-art analytical tools. They have developed a comprehensive AI engine that utilizes multiple medical data types to assist in identifying new disease patterns and the most promising therapeutic approaches, striving to achieve one of the most challenging global goals: health for all. info@topazium.com