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Cell:让“DNA剪刀”变身“RNA手术刀”!可爱龙团队将Cas9及其祖先转变为RNA编辑器
生物世界· 2025-08-19 04:02
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].
Wave Life Sciences .(WVE) - 2025 Q1 - Earnings Call Transcript
2025-05-08 13:32
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]