Oculis Holding Update Summary Company Overview - **Company**: Oculis Holding AG - **Ticker**: NasdaqGM: OCS - **Industry**: Biopharmaceuticals focusing on neuro-ophthalmology - **Market Potential**: Over $25 billion in neuro-ophthalmology with specific indications for OCS-05 targeting acute optic neuritis (AON) and non-arteritic anterior ischemic optic neuropathy (NAION) [4][12][14] Key Developments - **FDA Interaction**: Successful meeting with the U.S. FDA allowing OCS-05 to advance into the registration phase for AON and NAION [5][6] - **Registration Trials**: - **Pioneer 1**: Planned to start in Q4 2025 for AON - **Pioneer 2**: Planned to start in the first half of 2026 for AON - **Pioneer 3**: Planned to start in mid-2026 for NAION [6][7][15] Clinical Trial Design - **Pioneer Trials**: - Pioneer 1 and 2 will mirror the successful Phase 2 Acuity trial with the same dose and patient population [6][9] - Primary endpoint: Change from baseline in Low Contrast Visual Acuity (LCVA) at month three [10][12] - Secondary endpoints include the proportion of 15-letter gainers at month three and change from baseline in LCVA at month six [10][12] Market Opportunity - **Acute Optic Neuritis (AON)**: - Estimated 30,000 cases per year in the U.S. - Potential market size of over $3 billion with treatment costs between $100,000 to $400,000 per year [12][13] - **Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)**: - Estimated 30,000 to 35,000 cases per year in the U.S. - Potential market size of over $4 billion [14][15] Financial Position - **Balance Sheet**: Strong with no debt and cash runway extending to the end of 2027 without utilizing loan facilities [5] Strategic Focus - **Pipeline**: Multiple pivotal milestones focusing on significant unmet medical needs in neuro-ophthalmology [15][16] - **Future Plans**: - Launching Predict, a Phase 3 trial in genotype-based development for dry eye [15] - Aiming to leverage data from AON trials for potential MS relapse indications [9][15] Regulatory and Clinical Insights - **Regulatory Pathway**: Full alignment with FDA on trial designs and IND submissions for both AON and NAION [5][6] - **Patient Population**: Trials will include both MS and non-MS patients, with a focus on all-comers for AON [9][12] - **Treatment Window**: Treatment should ideally start within 12 days of symptom onset, with an average of 9.5 days observed in previous studies [61] Community Engagement - **Feedback from Neuro-Ophthalmologists**: Positive reception and engagement from the medical community regarding OCS-05, with plans for strong presence at upcoming medical congresses [73][74] Conclusion - Oculis is positioned to be a leader in neuro-ophthalmology with a robust pipeline and significant market opportunities in AON and NAION, aiming to address critical unmet medical needs while maintaining a strong financial foundation [15][16][60]

Core Viewpoint - Metformin, originally developed for type 2 diabetes, shows potential as a neuroprotective agent, particularly in the context of neurodegenerative diseases like multiple sclerosis, Parkinson's, and Alzheimer's [2][4][8]. Group 1: Research Findings - A recent study published in Nature Communications indicates that Metformin alters mitochondria-related metabolism and enhances the function of human oligodendrocytes, suggesting its neuroprotective effects [3][4]. - The study demonstrates that Metformin can penetrate the blood-brain barrier and promote functional regeneration of oligodendrocyte precursor cells (OPCs) in aged rats, enhancing myelin regeneration capabilities [8][9]. - In human stem cell-derived OPCs, Metformin increased the generation of myelin-related proteins, indicating its potential to stimulate myelin production in various cellular models [9]. Group 2: Clinical Implications - Clinical trials are currently underway to evaluate Metformin's efficacy as a treatment for multiple sclerosis, either as a monotherapy or in combination with other drugs, as well as its application as a direct neuroprotective agent for neurodegenerative diseases [8]. - Despite ongoing clinical trials, results have not yet been disclosed, and the specific effects of Metformin on human oligodendrocytes remain unclear, highlighting the need for further research [8][9].

Core Insights - The research identifies a new macrophage subpopulation, CX3CR1 and CD63 double-positive macrophages, that plays a crucial role in maintaining liver immune homeostasis [1][2][3] - The study utilizes advanced imaging techniques to analyze the spatial arrangement and molecular phenotype of macrophages in the liver, revealing their unique transcriptional characteristics [2] - The findings suggest that this macrophage subpopulation is not only vital for immune regulation but also provides neuroprotection, indicating its potential as a therapeutic target for liver-related diseases [2][3] Group 1 - The study was conducted by researchers from Hainan University, focusing on the liver's unique immune cell composition and the role of macrophages in immune homeostasis [1] - The liver is described as a unique immune organ composed of various immune cells, with macrophages being essential for maintaining immune balance [1][2] - The research highlights the significance of the liver portal area, where dysfunction is linked to various liver diseases, yet the immune cell subpopulations and their mechanisms remain poorly understood [1] Group 2 - The researchers employed the Liver-CUBIC optical clearing imaging technology to achieve single-cell resolution imaging of the liver [2] - The study found that the liver portal area macrophage subpopulation plays a key role in immune homeostasis and neuroprotection by interacting with T cells and sympathetic nerves [2] - In a non-alcoholic steatohepatitis mouse model, the absence of this macrophage subpopulation led to increased neutrophil infiltration and aggravated sympathetic nerve damage, underscoring its importance [2] Group 3 - The research provides new insights into the spatial heterogeneity of liver portal area macrophages, contributing to the fields of liver immunology and neuroimmunology [3] - The findings may lead to the development of more effective macrophage-targeted therapies aimed at restoring tissue integrity or treating organ-specific diseases [3] - The accompanying commentary in Nature Immunology emphasizes the strategic positioning of these macrophage subpopulations in maintaining organ integrity [3]

撰文丨王聪 编辑丨王多鱼 排版丨水成文 在 细胞 这个精密运转的"微型城市"中，信使RNA （mRNA） 分子如同快递包裹， 承载着生命活动的核心 指令，将来自 DNA 的遗传信息通过核糖体翻译为蛋白质，以执行生命活动。 N 6 -甲基 腺 苷 （ m 6 A ） 是 mRNA 中最常见的化学修饰 ，其在特定的 mRNA 中富集，并发挥着调节 细胞生长、分化和细胞应激反应的重要作用， m 6 A 是由包含 METTL3 和 METTL14 的异二聚体甲基转 移酶在 mRNA 上合成的。 m 6 A 的主要作用是促进 mRNA 的降解，因此，携带 m 6 A 的 mRNA 通常维 持在较低水平，而这些 mRNA 中的许多编码关键细胞过程的重要调控因子，其上调对于激活各种细胞反应 是必需的。 细胞应激反应依赖于由 m 6 A-mRNA 编码的蛋白质。例如，氨基酸耗竭压力会改变基因表达，以增强资源 的保存、恢复营养水平以及提高抗压能力。这些通路通常利用富含 m 6 A 的 mRNA，这些 mRNA 编码代 谢调控因子、DNA 修复通路蛋白和自噬蛋白。尽管已发现某些 mRNA 的水平在应激期间有所上升，但尚 不清楚这 ...