Rugonersen

撰文丨王聪编辑丨王多鱼排版丨水成文天使综合征（Angelman syndrome），是一种罕见的遗传性发育障碍疾病，约 20000 名新生儿中有一名患病。患病儿童有严重的智力障碍、癫痫发作、行走和睡眠障碍，以及缄默症（有些甚至一生中一言不发），脸上始终带着笑容，也因此得名。天使综合征是由位于 15 号染色体上的印迹基因 UBE3A 的突变或缺失导致的单基因遗传病，然而，其遗传学原理又比一般的单基因遗传病更为复杂。通常每个基因都有两个拷贝（一个来自父亲，一个来自母亲），这一对基因也被称为等位基因。而 UBE3A 基因比较特殊，其来自父亲的拷贝会被其反义链转录的长链 UBE3A-ATS 所沉默，所以只有来自母亲的拷贝表达。如果来自母亲的 UBE3A 基因出现问题（突变或缺失），就会导致患上天使综合征。对于这种复杂的遗传疾病，目前还没有根治方法，只能使用抗癫痫药物控制癫痫发作、以及进行运动、语言康复及行为教育。2025 年 7 月 11 日，罗氏公司（Roche）的研究人员在 Nature Medicine 期刊发表了：The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial 的研究论文。该临床试验达到了主要终点，Rugonersen 在天使综合征的治疗中具有可接受的安全性和耐受性特征。还显示出临床症状改善的迹象，这些初步临床结果支持 Rugonersen 在天使综合征治疗中的进一步开发。Rugonersen（RO7248824）是一种反义寡核苷酸（ASO）药物，通过靶向抑制 UBE3A-ATS，解除其对来自父亲的 UBE3A 基因的沉默作用，从而恢复表达。这项名为 TANGELO 的 1 期、多中心、开放标签、多剂量递增临床试验，旨在研究 Rugonersen 在 1-12 岁的天使综合征儿童患者（共 61 人，男女分别为 33 人和 28 人）中的安全性和耐受性（主要终点）以及药代动力学（次要终点）。评估 Rugonersen 治疗后变化的关键探索性终点指标为脑电图 δ 波功率（2-4 赫兹）以及 Bayley 婴幼儿发育量表（第三版）和 Vineland 适应行为量表（第三版）中的各个维度。结果显示，该临床试验达到了主要终点，Rugonersen 具有可接受的安全性和耐受性特征。对探索性终点的分析表明，Rugonersen 可导致天使综合征相关脑电图异常出现剂量依赖性的部分正常化，并显示出核心症状的临床改善的信号，超出了自然病史数据的预期。总的来说，这项初步临床试验的结果支持 Rugonersen 在天使综合征治疗中的进一步开发。论文链接：https://www.nature.com/articles/s41591-025-03784-7设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Oak Hill Bio, a biotechnology company focused on developing life-changing therapies for people with rare diseases, today announced the publication in Nature Medicine of the results of the rugonersen Phase 1 TANGELO study in 1 to 12 year old children with Angelman syndrome.1 Oak Hill Bio recently obtained exclusive rights to rugonersen and plans to initiate a Phase 3 study in patients with Angelman syndrome in early 2026. The results published today (The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial, Hipp et al., Nature Medicine, DOI 10.1038/s41591-025-03784-7) showed adverse event rates for rugonersen consistent with other antisense oligonucleotides, the route of administration, and the patient population. The results also showed that treatment with rugonersen led to dose-dependent partial normalization of pathological brain activity on a pharmacodynamic biomarker of brain function, electroencephalogram (EEG) delta power, and improvements on multiple exploratory endpoints measuring the core symptoms of Angelman syndrome as compared to natural history. The safety and tolerability profile, as well as the encouraging pharmacodynamic and exploratory clinical effects observed in TANGELO, provide strong support for further testing of rugonersen for the treatment of Angelman syndrome. “These promising results further support our decision to license exclusive rights to rugonersen. We are proud to support the continued development of this potential new treatment option," said Josh Distler, CEO of Oak Hill Bio. Angelman syndrome is caused by lack of the protein UBE3A in neurons due to a genetic defect on the maternal allele. UBE3A is expressed only from the maternal allele in neurons, while the paternal allele is silenced (imprinted) by a long non-coding antisense transcript (UBE3A-ATS) that interferes with the transcription of UBE3A from the paternal allele. Rugonersen (OHB-724) is designed to restore expression of UBE3A by suppressing the UBE3A-ATS transcript, thereby leveraging the intact paternal allele. TANGELO was a Phase 1, multicenter, open-label, multiple ascending, intra-patient dose escalation study that enrolled 61 patients aged 1-12 years with Angelman syndrome (mutation and deletion genotypes). In TANGELO, rugonersen led to a dose-dependent reduction in EEG delta power—a biomarker of abnormal brain activity in Angelman syndrome that has been shown to correlate with functional outcomes. The dynamics of the EEG biomarker provide robust pharmacodynamic data to inform the dose regimen of the planned Phase 3 trial. Exploratory clinical efficacy on developmental skills was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland). Four out of five behavioral domains tested by the Bayley-III and all five of the Vineland domains analyzed showed developmental gains above expectations from natural history. Of these results, most gains in developmental ability approached or surpassed thresholds for minimal clinically important group differences. “These are promising results that mark a major milestone in the development of disease-modifying therapies for Angelman syndrome,” said Dr. Mark Shen, Assistant Professor of Neuroscience and Psychiatry at the University of North Carolina School of Medicine and one of the principal investigators and authors of the paper. “In this paper, we have shown that an investigational treatment targeting the root cause of a genetic neurodevelopmental disorder can improve both brain activity and behavioral symptoms as compared to natural history in a consistent and measurable way.” “Although these results are exploratory, rugonersen shows promise based upon the evidence published today of improvements in both a neurophysiologic biomarker and functional endpoints in individuals with Angelman syndrome,” said Dr. Wen-Hann Tan, Attending Physician, Division of Genetics and Genomics at Boston Children’s Hospital and Associate Professor of Pediatrics at Harvard Medical School, an expert on Angelman syndrome, who was not involved in the study. “These results provide support for further investigation of rugonersen and UBE3A-targeting strategies in randomized controlled trials and highlight the potential value of EEG as a biomarker.” Angelman syndrome affects an estimated 500,000 individuals worldwide. It typically presents during early childhood and is characterized by cognitive and developmental issues, including speech and communication difficulties, motor impairment, balance issues, and debilitating seizures. Rugonersen was generally well tolerated across more than 450 intrathecal administrations among 61 participants, some of whom received treatment for up to four years. The most common adverse events (AEs) were transient pyrexia and vomiting, typically occurring shortly after dosing. Serious adverse events (SAEs) were experienced by 34% of participants and those deemed related to treatment occurred in 13% of participants (or 2% of administrations). Treatment-related SAEs included seizure, epilepsy, vomiting, pyrexia and post-lumbar puncture syndrome. No participants were withdrawn from the study due to AEs. “These promising results further support our decision to license exclusive rights to rugonersen. We are proud to support the continued development of this potential new treatment option and are deeply appreciative of the patients, families, and investigators whose commitment made this work possible,” said Josh Distler, Chief Executive Officer of Oak Hill Bio. “This publication in Nature Medicine reflects the strength of the science and the importance of advancing treatments that can meaningfully improve the lives of people living with Angelman syndrome and their families.” About Oak Hill Bio Oak Hill Bio is a clinical-stage biotechnology company dedicated to developing life-changing therapies for people with rare diseases. Its pipeline includes late-stage programs in Angelman syndrome and complications of extreme prematurity, as well as a preclinical asset for diabetic macular edema. For more information, visit www.oakhillbio.com. 1 This study was sponsored and conducted by Roche.