编辑丨王多鱼 排版丨水成文 RNA 编辑 具有 可逆 和不 改变基因组序列的 特性 ，在基础研究和疾病治疗领域展现出独特优势 。然而，现有 RNA 碱基编辑工具大多局限于 " 单点编辑 "， 难 以 应对涉及多个核苷酸的复杂调控 。因此，开发能够在 一定 区域内实现多碱基 可控 编辑的新工具，对于拓展 RNA 编辑的应用 范围 具有重要意义。 2026 年 1 月 2 日，北京大学 伊成器 团队 （ 庄元 、 朱擎国 、 乌浩 、 林湘玥 为论文共同第一作者 ） 在 Nature Biotechnology 期刊 发表了题为： Single- strand deaminase-assisted editing for functional RNA manipulation 的研究论文。 该研究建立了 由单链脱氨酶辅助的可调节 RNA 信息操纵平台—— AIM （ a djustable RNA i nformation m anipulation ） 。 该平台突破了目前 RNA 碱基编辑 工具 " 单点编辑 " 的限制，实现了在 RNA 靶向 区域内对 不同数量、多种类型 碱基 的 可控与精准操纵，为 RN ...

Core Insights - The ADAR (Adenosine deaminases acting on RNA) family plays a crucial role in RNA A-to-I editing, regulating RNA diversity, immune homeostasis, and neural function [3] - ADAR-based RNA editing technology has rapidly developed, offering advantages over CRISPR gene editing, such as avoiding the introduction of foreign editing enzymes and related immunogenicity issues, making it a promising candidate for genetic disease therapies [3] - Mutations in the ADAR1 gene can lead to autoimmune diseases, such as Aicardi-Goutières syndrome, by editing the host's double-stranded RNA (dsRNA) to prevent unnecessary autoimmune responses [3] Research Findings - A series of studies published in Nature in July 2022 elucidated the downstream pathways of ADAR1 gene mutations leading to autoinflammation, identifying ZBP1 as a key effector factor in cell death and inflammation transcription [4][6] - Research from Stanford University highlighted that ADAR1-mediated RNA A-to-I editing is a critical post-transcriptional event preventing innate immune interferon responses triggered by self dsRNA, with reduced editing levels due to genetic factors increasing the risk of inflammatory diseases [8] - A study published in Nature Cancer in February 2025 identified ADAR1 as a druggable target in prostate cancer, leading to the development of the small molecule inhibitor ZYS-1, which demonstrated significant anti-tumor effects and good safety profiles [9] Drug Development and Applications - Extensive research indicates that ADAR1 is not only an RNA editing enzyme but also closely related to autoimmune diseases and cancer, making it an important drug target [12] - Strategies for developing ADAR1-targeted inhibitors include targeting its catalytic domain, regulating upstream and downstream signaling pathways, and employing PROTAC degradation technology, showing broad prospects in treating cancer and autoimmune diseases [12] - A live lecture organized by BioWorld and Yi Qiao Shen Zhou will discuss the role of ADAR-mediated RNA editing in cancer therapy and the significance of ADAR1 as a drug target, featuring insights from experts in the field [12]

Core Viewpoint - Wave Life Sciences Ltd reported disappointing third-quarter financial results, missing both earnings and sales expectations, but highlighted significant clinical progress in its pipeline, particularly with WVE-007 for obesity and WVE-006 for alpha-1 antitrypsin deficiency [1][2]. Financial Performance - The company reported quarterly losses of $0.32 per share, which was worse than the analyst consensus estimate of losses of $0.30 per share [1]. - Quarterly sales amounted to $7.608 million, falling short of the analyst consensus estimate of $11.130 million [1]. Clinical Developments - Wave Life Sciences achieved key clinical objectives with WVE-007 and WVE-006, reinforcing its leadership in RNAi and RNA editing [2]. - WVE-007 is positioned to potentially disrupt the obesity treatment landscape, offering advantages such as fat loss induction, muscle preservation, and improved cardiometabolic health with less frequent dosing compared to existing treatments [2]. Analyst Ratings and Price Targets - Following the earnings announcement, analysts adjusted their price targets for Wave Life Sciences: - Wells Fargo maintained an Overweight rating but lowered the price target from $18 to $16 [5]. - Wedbush maintained an Outperform rating and raised the price target from $18 to $20 [5]. Market Reaction - Following the announcement, Wave Life Sciences shares increased by 3.1%, trading at $7.26 [2].

Summary of Wave Life Sciences' 2025 Research Day Company Overview - **Company**: Wave Life Sciences - **Focus**: RNA editing and RNA interference (RNAi) therapeutics - **Vision**: Deliver high-impact medicines and innovate in oligonucleotide therapeutics and human health [3][4] Key Highlights Emerging Pipeline and Innovations - **Pipeline**: Multimodal pipeline of RNA medicines leveraging AI for target discovery and development [4] - **Clinical Trials**: Updates on ongoing clinical trials, particularly RESTORATION2 for WVE-006 and INLIGHT for WVE-007 [4][5] RNA Editing and Clinical Programs - **WVE-006**: A first-in-class RNA editing therapy for Alpha-1 Antitrypsin Deficiency (AATD) - **Clinical Data**: Positive results from RESTORATION2 trial showing restoration of AAT protein levels necessary to prevent lung damage [5][15] - **Key Metrics**: Achieved AAT levels up to 13 micromolar, with 64% being wild-type MAAT and a 60% decrease in mutant Z protein [16] - **Dosing**: Potential for monthly or less frequent dosing due to sustained effects [16][18] - **WVE-008**: New RNA editing candidate targeting PNPLA3 for liver disease - **Target Population**: Approximately 9 million homozygous I148M carriers in the U.S. and Europe at high risk for liver disease [20] - **Mechanism**: Aims to correct the I148M variant to restore normal PNPLA3 function, addressing steatosis and fibrosis [21][30] - **Clinical Development**: CTA submission planned for 2026 [31] Obesity Program - **WVE-007**: A GalNAc-conjugated siRNA targeting INHBE for obesity treatment - **Mechanism**: Designed to promote fat loss while preserving muscle mass [32][33] - **Clinical Data**: INLIGHT trial shows significant dose-dependent reductions in activin E, with 85% reduction at 400 mg [48] - **Expected Outcomes**: Aiming for weight loss competitive with semaglutide, focusing on visceral fat reduction [52] Platform Innovations - **SPiNA Technology**: New design for siRNA that enhances AGO2 loading, improving potency and durability [55][56] - **Tissue Targeting**: Ability to access various tissues, including liver and adipose, for effective silencing of target genes [58][59] Market Potential - **Addressable Population**: Potential to treat over 100 million people in the U.S. and Europe with genetic insights driving the pipeline [8] - **Unmet Needs**: Focus on diseases with high unmet medical needs, particularly in liver and obesity-related conditions [30][31] Conclusion - Wave Life Sciences is positioned to make significant advancements in RNA therapeutics, with promising clinical data supporting its innovative approaches to treating genetic diseases and obesity. The company is on track for multiple clinical updates in the coming years, with a strong emphasis on precision medicine and addressing unmet medical needs in large patient populations [3][4][8][30].

Core Insights - Wave Life Sciences Ltd. is experiencing a decline in stock price following the release of data from the Phase 1b/2a RestorAATion-2 Trial of WVE-006 for alpha-1 antitrypsin deficiency [1] - The company is facing selling pressure in the market [1] Trial Data Summary - The reported data includes results from RestorAATion-2 cohort 1 (200 mg, n=8) where participants received a single subcutaneous dose of WVE-006 followed by seven subcutaneous doses every other week, and the single dose portion of cohort 2 (400 mg, n=8) [2] - WVE-006 demonstrated RNA editing in all treated participants, leading to durable production of serum AAT at levels associated with a lower risk of liver and lung disease after repeat 200 mg doses [3] - Data from both the 200 mg and 400 mg cohorts support a monthly or less frequent subcutaneous dosing regimen, with ongoing dosing in the 400 mg multidose cohort expected to deliver data in the first quarter of 2026 [3] Safety and Licensing - WVE-006 has shown a favorable safety profile and continues to be well-tolerated [4] - GSK Plc holds the exclusive global license for WVE-006, with development and commercialization responsibilities transferring to GSK after the completion of the RestorAATion-2 study [4] Future Developments - Wave Life Sciences is advancing a wholly owned pipeline of RNA editing candidates, with plans to share new preclinical data at Research Day in fall 2025 and to initiate clinical development of additional RNA editing programs in 2026 [5] - As of the publication date, WVE stock is down 21.41% at $7.56 [5]

Core Viewpoint - The research presents a novel RNA editing tool, R-IscB, engineered from the Cas9 ancestor IscB, which offers a safer and more efficient alternative to existing RNA editing technologies like Cas13, addressing the limitations of current methods in clinical applications [3][4][16]. Group 1: RNA Editing Technology - CRISPR-Cas9 has revolutionized genome medicine but poses irreversible DNA editing risks, limiting its clinical use [3]. - RNA editing is a safer alternative due to its transient and reversible nature, but existing tools like CRISPR-Cas13 face significant challenges, including off-target effects and cellular toxicity [3][4]. - The study by Yale University transformed IscB and Cas9 into RNA-guided RNA editors, demonstrating potential applications in splice interference, trans-splicing, and RNA base editing [4][16]. Group 2: Engineering and Mechanism - The research team engineered IscB by removing its TID/PID domains, converting it into R-IscB, which retains the ability to recognize single-stranded DNA/RNA while losing its double-stranded DNA cutting capability [8][14]. - R-IscB exhibits a strong affinity for single-stranded RNA, surpassing Cas13 in performance [8][12]. Group 3: Applications and Efficacy - R-IscB has shown effectiveness in various applications: 1. RNA splicing regulation, significantly reducing pathogenic mRNA levels [10]. 2. Trans-splicing capabilities to correct mutations in mRNA, potentially simplifying treatments for complex genetic disorders [11]. 3. RNA base editing for precise single nucleotide changes, useful for correcting disease-causing mutations [11]. 4. RNA degradation through enhanced cutting activity, effectively lowering target mRNA levels [11]. Group 4: Advantages Over Cas13 - R-IscB presents several disruptive advantages compared to Cas13: 1. Zero toxicity, with no observed cell death or morphological abnormalities in treated cells [13]. 2. Superior activity in splicing regulation and RNA cutting [13]. 3. Smaller size, facilitating easier delivery via AAV viral vectors for in vivo RNA editing [13]. 4. Versatility, as the same engineering strategy successfully enhanced RNA editing capabilities in multiple Cas9 variants [13][14].

Financial Data and Key Metrics Changes - Revenue for Q1 2025 was $9.2 million, down from $12.5 million in the same quarter last year, attributed to the timing of revenue recognition under the collaboration agreement with GSK [34] - Research and development expenses increased to $40.6 million from $33.4 million year-over-year, driven by spending on the Inhibin E program and RNA editing programs [34] - General and administrative expenses rose to $18.4 million from $13.5 million, primarily due to share-based compensation and professional fees [35] - The net loss for Q1 2025 was $46.9 million, compared to a net loss of $31.6 million in the prior year quarter [35] - Cash and cash equivalents at the end of Q1 2025 were $243.1 million, down from $302.1 million as of December 31, 2024, with expectations to fund operations into 2027 [36] Business Line Data and Key Metrics Changes - The company is advancing its clinical pipeline, particularly in obesity and AATD (Alpha-1 Antitrypsin Deficiency) programs, with significant progress reported in clinical trials [7][9] - WVE-007 for obesity is designed to provide sustainable weight loss with infrequent dosing, showing promising preclinical data [10][28] - WVE-006 for AATD aims to be the first treatment addressing the root cause of the disease, with ongoing trials demonstrating well-tolerated results and potential for extended dosing intervals [12][14] Market Data and Key Metrics Changes - The obesity treatment market is seeing rapid advancements, with WVE-007 positioned to compete against GLP-1s, which have limitations such as frequent dosing and side effects [10][29] - The DMD (Duchenne Muscular Dystrophy) market has an urgent need for effective therapies, with approximately 20,000 new cases annually and a significant portion of patients remaining untreated [19][20] - The company reported that sales of exon skipping therapies reached approximately $1.1 billion in 2024, highlighting the market potential for its DMD treatment [20] Company Strategy and Development Direction - The company is focused on unlocking the potential of RNA medicines, with a multimodal pipeline that includes programs for obesity, AATD, DMD, and Huntington's disease [7][8] - Plans to submit an NDA for WVE-531 in 2026 for accelerated approval, emphasizing the importance of dystrophin expression as a surrogate endpoint [21][84] - The company aims to differentiate its therapies by demonstrating comprehensive clinical benefits, including muscle health improvements and reduced fibrosis [75] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the ongoing clinical trials and the potential for significant milestones throughout 2025, including data on healthy weight loss and RNA editing [38] - The company is actively engaging with the FDA regarding its accelerated approval pathways and is committed to providing comprehensive data to support its filings [44][86] - There is a recognition of the evolving landscape in gene therapy and the need for effective communication with clinicians regarding treatment options for DMD [93] Other Important Information - The company is advancing a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets, with plans to initiate clinical development of new programs in 2026 [30][33] - Upcoming data presentations at medical meetings are expected to provide insights into the efficacy and safety of the company's RNA editing programs [16][32] Q&A Session Summary Question: What triggers data disclosure for the Inhibin E program? - The company will look at time points such as one month, three months, and six months for data disclosure, with an internal cutoff for data analysis [40][42] Question: Are all drugs slated for accelerated approval under CDER? - Yes, the company confirmed that its drugs are under CDER, and discussions with the agency have remained consistent regarding the accelerated approval pathway [43][84] Question: What are the benefits of RNA editing versus DNA editing for AATD? - RNA editing avoids bystander edits and potential irreversible collateral effects associated with DNA editing, making it a safer option for patients [57][60] Question: How many additional DMD patients are needed for the monthly dosing regimen? - The company is currently enrolling patients and expects to provide updates on the number needed for the monthly dosing regimen [91][92] Question: Is the plan for using dystrophin expression for accelerated approval locked in? - The agency has indicated that dystrophin is a clinical surrogate endpoint for accelerated approval, but there is always a risk of changes with new leadership at the agency [84][86]