A Phase 1/2, Open-label, Multi-national, Multiple-cohort, Dose-escalation Study to Evaluate the Safety, Tolerability, and Efficacy of HG004 Gene Therapy in Subjects with RPE65-associated Leber Congenital Amaurosis Type 2 (LCA2)

The purpose of the study is to determine whether HG004 as gene therapy is safe and effective for the treatment of Leber Congenital Amaurosis caused by mutations in RPE65 gene.

开始日期2023-10-31

申办/合作机构

辉大（上海）生物科技有限公司初创企业

CTR20232920 / Recruiting临床1/2期

一项评价HG004基因治疗产品在RPE65突变相关的2型Leber’s先天性黑矇（LCA2）受试者中的安全性、耐受性和疗效的Ⅰ/Ⅱ期、国际多中心、开放标签、多队列、剂量递增临床研究

评价HG004在RPE65基因突变引起的Leber’s先天性黑矇受试者中的安全性和疗效性

开始日期2023-10-25

申办/合作机构

辉大（上海）生物科技有限公司初创企业

NCT06064565 / Recruiting早期临床1期

An Investigator-Initiated Open-Label, Multiple-Dose Clinical Study to Evaluate the Safety, Tolerability, and Efficacy of Gene Therapy for 2 Leber's Congenital Amaurosis With RPE65 Mutation (LCA2)

The purpose of the study is to determine whether HG004 as gene therapy is safe and effective for the treatment of Leber Congenital Amaurosis caused by mutations in RPE65 gene.

开始日期2023-01-10

申办/合作机构

辉大（上海）生物科技有限公司初创企业

100 项与 HG-004 相关的临床结果

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100 项与 HG-004 相关的转化医学

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100 项与 HG-004 相关的专利（医药）

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项与 HG-004 相关的文献（医药）

Cardiovascular diabetology

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway

Article

作者: Cao, Lei ; Cui, Jianlin ; Liu, Chunlei ; Liu, Jie ; Shen, Yanna ; Zhang, Qian ; Zhang, Shengzheng ; Yang, Liang ; Wang, Ziwei ; Li, Guangru ; Feng, Lifeng ; Li, Jing ; Zhang, Junwei ; Liu, Chang ; Yan, Jie ; Qi, Zhi ; Duan, Xianxian ; Gao, Yang ; Tian, Wencong ; Xu, Yang

Abstract:

Aims:

Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms.

Methods and results:

We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B−/− mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes.

Conclusions:

These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

项与 HG-004 相关的新闻（医药）

2024-11-05

·PipelineReview

HuidaGene Therapeutics Receives the First-Ever FDA Clearance of CRISPR/Cas13 RNA-Editing HG202 for Macular Degeneration

SHANGHAI, China and CLINTON, NJ, USA I November 4, 2024 I HuidaGene Therapeutics (“HuidaGene”), a global clinical-stage biotechnology company, announced that the U.S. FDA has cleared its investigational new drug (IND) application for HG202, the world’s first-ever CRISPR/Cas13 RNA-editing therapy for clinical use in treating neovascular age-related macular degeneration (nAMD), which affects millions worldwide. “This open IND for HG202 by the U.S. FDA-the first regulator to clear CRISPR/Cas13 for clinical development–marks a significant milestone for HuidaGene and the CRISPR RNA-editing field,” noted Alvin Luk, Ph.D., M.B.A., C.C.R.A., Co-founder and CEO of HuidaGene. “The strong preclinical data for HG202, combined with promising results from the first-in-human ‘ SIGHT-I ‘ trial in China, underscored its potential to address AMD using a non-receptor binding pathway through the Cas13 RNA editor to knockdown VEGF-A mRNA.” Xin Zhang, M.D., MSc., COO and CMO of HuidaGene, highlighted the urgency of new nAMD treatments: “Up to 46% of AMD patients respond poorly or develop resistance to anti-VEGF therapies. AMD patients deserve safe, effective treatment options. The BRIGHT trial will evaluate HG202’s safety and efficacy to address this gap. We look forward to enrolling patients soon.” “Our AI/ML-driven HG-PRECISE® platform led us to discover the Cas13X/Y system ( Nature Methods 2021),” added Hui Yang, Ph.D., Co-Founder and Chief Scientific Advisor of HuidaGene. “Building on this basis, my team engineered high-fidelity Cas13Y with efficient editing and low off-target effects ( Nature Biotechnology 2022), laying out the technical foundation for future clinical applications.” BRIGHT Trial of HG202 (NCT06623279) The BRIGHT (an open-la B el, dose-escalation study for CRISPR/Cas13- R NA target I n G t H erapy for the T reatment of neovascular AMD) trial, a Phase 1, dose-finding study, will investigate the safety and efficacy of HG202 at different doses in nAMD patients. Primary endpoints include the safety and tolerability of HG202, with secondary endpoints assessing improvements in visual acuity, retinal thickness, and the need for anti-VEGF injections. About HuidaGene HuidaGene utilizes its proprietary CRISPR-based HG-PRECISE® platform to develop potentially curative genome medicines. The Company is advancing clinical programs, including trials of HG004 (granted ODD & RPDD by FDA) ‘ LIGHT ‘ trial (NCT06088992) and Phase 1/2 international, master-protocol ‘ STAR ‘ clinical trial (NCT05906953) for RPE65 -associated retinal disease, HG202 RNA-editing therapy ‘ SIGHT-I ‘ first-in-human trial (NCT06031727) and ‘ BRIGHT ‘ Phase 1 clinical trial (NCT06623279) for nAMD, HG204 RNA-editing therapy (granted ODD & RPDD by FDA and ODD by EMA) ‘ HERO ‘ trial (NCT06615206) for MECP2 duplication syndrome, and HG302 DNA-editing therapy (granted ODD & RPDD by FDA) first-in-human ‘ MUSCLE ‘ trial (NCT06594094) for DMD. The preclinical programs include HG303 DNA-editing for ALS and CRISPR RNA-editing therapy for Alzheimer’s. With an extensive intellectual property portfolio, HuidaGene is a leader in genome medicines for neurology and ophthalmology. Learn more at huidagene.com or on LinkedIn . SOURCE: HuidaGene Therapeutics

临床申请临床1期siRNA

2024-11-04

·PRNewswire

HuidaGene Therapeutics Receives the First-Ever FDA Clearance of CRISPR/Cas13 RNA-Editing HG202 for Macular Degeneration

HG202 is the first CRISPR/Cas13Y RNA-targeting therapy to enter clinical development and the only clinical-stage CRISPR RNA-editing therapy for age-related macular degeneration Preclinical studies in laser-induced CNV mice showed HG202 reduced CNV area by 87%, outperforming both anti-VEGF antibodies and AAV-anti-VEGF gene therapy SHANGHAI and CLINTON, N.J., Nov. 4, 2024 /PRNewswire/ -- HuidaGene Therapeutics ("HuidaGene"), a global clinical-stage biotechnology company, announced that the U.S. FDA has cleared its investigational new drug (IND) application for HG202, the world's first-ever CRISPR/Cas13 RNA-editing therapy for clinical use in treating neovascular age-related macular degeneration (nAMD), which affects millions worldwide. "This open IND for HG202 by the U.S. FDA-the first regulator to clear CRISPR/Cas13 for clinical development–marks a significant milestone for HuidaGene and the CRISPR RNA-editing field," noted Alvin Luk, Ph.D., M.B.A., C.C.R.A., Co-founder and CEO of HuidaGene. "The strong preclinical data for HG202, combined with promising results from the first-in-human ' SIGHT-I' trial in China, underscored its potential to address AMD using a non-receptor binding pathway through the Cas13 RNA editor to knockdown VEGF-A mRNA." Xin Zhang, M.D., MSc., COO and CMO of HuidaGene, highlighted the urgency of new nAMD treatments: "Up to 46% of AMD patients respond poorly or develop resistance to anti-VEGF therapies. AMD patients deserve safe, effective treatment options. The BRIGHT trial will evaluate HG202's safety and efficacy to address this gap. We look forward to enrolling patients soon." "Our AI/ML-driven HG-PRECISE® platform led us to discover the Cas13X/Y system (Nature Methods 2021)," added Hui Yang, Ph.D., Co-Founder and Chief Scientific Advisor of HuidaGene. "Building on this basis, my team engineered high-fidelity Cas13Y with efficient editing and low off-target effects (Nature Biotechnology 2022), laying out the technical foundation for future clinical applications." BRIGHT Trial of HG202 (NCT06623279) The BRIGHT (an open-la Bel, dose-escalation study for CRISPR/Cas13- RNA target In G t Herapy for the Treatment of neovascular AMD) trial, a Phase 1, dose-finding study, will investigate the safety and efficacy of HG202 at different doses in nAMD patients. Primary endpoints include the safety and tolerability of HG202, with secondary endpoints assessing improvements in visual acuity, retinal thickness, and the need for anti-VEGF injections. About HuidaGene HuidaGene utilizes its proprietary CRISPR-based HG-PRECISE® platform to develop potentially curative genome medicines. The Company is advancing clinical programs, including trials of HG004 (granted ODD & RPDD by FDA) ' LIGHT' trial (NCT06088992) and Phase 1/2 international, master-protocol ' STAR' clinical trial (NCT05906953) for RPE65-associated retinal disease, HG202 RNA-editing therapy ' SIGHT-I' first-in-human trial (NCT06031727) and ' BRIGHT' Phase 1 clinical trial (NCT06623279) for nAMD, HG204 RNA-editing therapy (granted ODD & RPDD by FDA and ODD by EMA) ' HERO' trial (NCT06615206) for MECP2 duplication syndrome, and HG302 DNA-editing therapy (granted ODD & RPDD by FDA) first-in-human ' MUSCLE' trial (NCT06594094) for DMD. The preclinical programs include HG303 DNA-editing for ALS and CRISPR RNA-editing therapy for Alzheimer's. With an extensive intellectual property portfolio, HuidaGene is a leader in genome medicines for neurology and ophthalmology. Learn more at huidagene.com or on LinkedIn. SOURCE HuidaGene Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床申请临床1期siRNA

2024-11-04

·凯莱英药闻

首个且唯一! 辉大基因CRISPR/Cas13 RNA编辑疗法IND获FDA批准

欢迎关注凯莱英药闻 2024年11月4日，辉大基因宣布，其开发的HG202的新药临床试验申请（IND）已获得美国FDA批准，用于新生血管性年龄相关性黄斑变性（nAMD）。HG202是首个进入临床阶段的CRISPR/Cas13 RNA编辑疗法，也是唯一针对湿性年龄相关性黄斑变性 (nAMD) 的临床阶段RNA靶向治疗。关于HG202 作为一种“一次性”疗法，HG202有望产生更强大和持久的疗效，且对目前常规临床使用的连续玻璃体内抗 VEGF 药物反应不佳的患者有益。 SIGHT-I 是一项开放标签、多中心和剂量递增研究，旨在通过评估患者在采用HG202不同剂量下的安全性和耐受性。研究显示，截至 2024 年 3 月，低剂量队列的第一名受试者在 8 个月内曾注射过 6 次抗 VEGF注射，注射前黄斑积液持续存在，在基线包括CRT 为 233 µm 和 BCVA 为 29 个字母。注射后视网膜液明显消除，注射后4周和8周CRT分别恢复到162和155µm。从注射后第4周开始观察到近15个字母的BCVA改善，并持续到注射后第8周。在安全性上，低剂量组中的三名参与者在注射 HG202 后 4 至 6 个月内接受随访，并持续观察。未报告与 AAV 或 CRISPR/Cas13 相关的药物相关严重不良事件，也未报告炎症或急性视网膜毒性迹象。与视网膜下手术相关的不良事件大多是轻微和短暂的，无需任何干预即可解决。此外，激光诱导CNV小鼠的临床前研究表明，HG202的递送使CNV面积减少87%，优于抗VEGF抗体和AAV抗VEGF基因疗法。关于黄斑变性随着全球人口老龄化的加剧，眼科疾病的患者和市场正在逐年增加，年龄相关黄斑变性（AMD）、糖尿病黄斑水肿（DME）和视网膜静脉阻塞（RVO）这三种视网膜疾病，影响了全球约7000 万人，是视力丧失的主要原因之一。根据弗若斯特沙利文数据，2020 年美国的湿性老年性黄斑变性（wAMD）患者人数达到186.65 万，预计到2025 年将达到197.29 万，到2030 年将达到207.73万。在中国，湿性老年性黄斑变性的患病率从2016 年的329 万例增长至2020 年的376 万例，复合年增长率为3.4%，预计到2025 年将进一步增长至432 万例，2020 年至2025 年的复合年增长率为2.8%。中国及美国湿性老年性黄斑变性患病人数及预测（万人）血管内皮生长因子（VEGF）的高表达与新生血管性视网膜疾病的发生发展密切相关，抗VEGF 眼科药物成为治疗视网膜病变的标准疗法。目前全球有5 款抗VEGF 眼科药物获批上市，分别是雷珠单抗（Lucentis）、阿柏西普（Eylea）、布西珠单抗（Beovu）和法瑞西单抗。从药物销售额来看，全球抗VEGF 眼科用药市场销售额呈增长态势，2022 年超过170 亿美元。其中雷珠单抗全球销售额连续5 年超30 亿美元，阿柏西普全球销售额呈快速增长态势，2022 年销售额达136.15 亿美元，成为全球最畅销的抗VEGF 眼科药物。法瑞西单抗自2022 年1 月上市以来，销售额表现不错，2022年全球销售额达到6.20 亿美元，2023 年总销售额高达26.67 亿美元。抗VEGF 眼科生物药全球销售额（亿美元）目前湿性老年性黄斑变性适应症患者的治疗选择主要为VEGF 单抗疗法，单靶点抗VEGF 疗法面临的一个主要挑战是当抑制VEGF 通路时，其他促血管生成因子（如FGF-2）的表达可能被上调，从而限制单靶点VEGF 抑制剂的疗效。同时还有给药频率等因素影响，wAMD 和DME 患者的临床需求尚未被完全满足，患者亟需疗效更优、风险更小、更加便捷的抗VEGF 药物。关于基因编辑疗法基因编辑是指用可编辑的核酸酶识别基因组特定位点并介导DNA 双链断裂，随后诱发内源性DNA 修复机制，从而实现对DNA 序列的定点修饰的技术，包括靶向敲除或插入基因。基因编辑本质上是一种技术手段，由于多种疾病的发生与基因的错误表达直接相关，因此该技术有望实现疾病治疗。目前，基因编辑工具手段经历了ZFNs 技术、TALENs 技术、CRISPR技术的更新迭代发展；完成序列的识别与剪切所依靠的基因编辑工具是各个企业研发重点，识别效率与剪切准确率是决定最终治疗效果的关键。 CRISPR 技术来源于细菌抵御外来噬菌体入侵的机制，细菌通过识别噬菌体的DNA 结构进而完成剪切。CRISPR 的识别DNA 序列由sgRNA 完成，该结构由crRNA和tracrRNA 两部分组成，切割由Cas9 蛋白完成。由于该机制中识别位点的特异性由RNA 决定而并非蛋白质，因此操作更加简单便宜，且可以剪切多个位点，是目前最便捷、应用最广泛的基因编辑工具。CRISPR 技术仍然在向外衍生，例如可更换Cas 蛋白，从Cas9 更换至Cas12、Cas13 等，以图更精确地剪切目标序列。目前，大部分关于CRISPR/Cas9 的专利技术，基本属于国外。围绕专利相关的壁垒，国内企业一部分选择基于底层技术进行创新，一部分则选择在众多的家族蛋白中，选择其他Cas 蛋白进行研究和突破。其中，以CRISPR/Cas12、CRISPR/Cas13 基因编辑技术的研究较多。 CRISPR/Cas13属于CRISPR/Cas系统中的第二大类VI型，包含单一的效应蛋白质Cas13，与crispr RNA(crRNA)组装时形成一个由crRNA引导的RNA靶向效应复合物。截至目前，共发现有6种效应蛋白属于CRISPR/Cas13家族，即Cas13a、Cas13b、Cas13c、Cas13d、Cas13X和Cas13Y。Cas13蛋白不需要反式激活RNA(tracr RNA)或内源性核糖核酸酶(RNase)，其本身具有两种不同的RNase活性，分别是将pre-crRNA预处理成成熟的crRNA和对靶标RNA进行剪切。依赖于Cas13非特异的RNA切割能力，Cas13已被开发为体外核酸检测的高灵敏度诊断工具；此外，核酸编辑有望治疗遗传疾病，特别是在RNA水平的编辑，可以敲除疾病相关序列而使致病的功能性蛋白无法翻译。与DNA碱基编辑相比，RNA碱基编辑不稳定且更容易逆转，并允许对编辑过程进行精细的控制。此外DNA编辑会影响所有转录产物，而RNA编辑时编辑和非编辑的转录产物可以同时存在，这相当于实现了一定的编辑剂量控制，并避免围绕基因组编辑产生的伦理问题。关于辉大基因辉大基因利用其专有的HG-PRECISE®平台来发现、设计和开发新的CRISPR基因疗法。公司正在推进多个临床项目，包括HG004、HG202、HG204以及HG302 DNA编辑疗法；临床前项目还包括针对ALS的HG303 DNA编辑以及针对阿尔茨海默病的CRISPR RNA编辑疗法。辉大基因拥有着丰富且深度的知识产权组合布局，正在成为神经和眼科基因治疗领域的领导者。参考资料 1、公司官网 2、招商证券、东海证券、蛋壳研究院 3、莱博集团感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

基因疗法临床申请上市批准

100 项与 HG-004 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
双等位基因RPE65突变相关的视网膜变性疾病	临床2期	美国	辉大（上海）生物科技有限公司初创企业	2023-10-31
双等位基因RPE65突变相关的视网膜变性疾病	临床2期	中国	辉大（上海）生物科技有限公司初创企业	2023-10-31
2型利伯先天性黑朦症	临床2期	中国	辉大（上海）生物科技有限公司初创企业	2023-10-25

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临床结果

适应症

分期

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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


EURETINA2024	N/A	视网膜变性疾病	-	HG004 (AAV9-hRPE65)HG004 (AAV9-RPE65)) (HG004 (AAV9-RPE65) low dose)	鑰鏇鹹積夢鹽膚鹹簾壓(範範憲窪願蓋簾選糧廠) = 遞製網願鬱淵鹽鏇顧顧壓淵窪觸齋餘顧艱鹽網 (網夢艱餘鑰壓膚構遞鬱 )	-	2024-09-19
NCT06088992 (LIGHT, ASGCT2024) 人工标引	临床1/2期	莱伯先天性黑蒙 RPE65 Gene Mutation	9	HG004 (in the worst eye at low dose)	繭鏇憲齋構衊壓鑰淵壓(憲遞蓋繭窪淵窪築醖壓) = Most were mild and transient which have resolved without any intervention. No signs of inflammation or acute retinal toxicity after the injection of HG004. 齋淵鏇積糧衊繭淵鑰鹹 (艱築醖遞壓遞網廠餘憲 )	积极	2024-04-23
NCT06088992 (LIGHT, ASGCT2024) 人工标引	临床1/2期	莱伯先天性黑蒙 RPE65 Gene Mutation	9	HG004 (in the worst eye at middle dose)		积极	2024-04-23