Tetracycline Hydrochloride

Highlights include clinical data from Phase 3 studies in Community Acquired Pneumonia (CABP) and microbiologic data from a Phase 2 study in nontuberculous mycobacterial pulmonary disease (NTM-PD) caused by Mycobacterium abscessus complex (MABc), as well as additional clinical and non-clinical data from Company- and investigator-sponsored studies KING OF PRUSSIA, Pa. and BOSTON, Oct. 17, 2025 (GLOBE NEWSWIRE) -- Paratek Pharmaceuticals, Inc., a privately held pharmaceutical company focused on the development and commercialization of specialty therapies for specialists and community care providers that address public health threats and important unmet medical needs, today announced that new data from clinical studies of NUZYRA® (omadacycline) will be presented at IDWeek 2025 in Atlanta, GA, and CHEST 2025 in Chicago, IL, both meetings being held October 19-22. “The upcoming presentations at two major conferences will provide the medical community a broad window into understanding NUZYRA’s potential utility against serious, community-acquired infections,” said Randy Brenner, chief development and regulatory officer of Paratek. “At CHEST, an oral presentation will report quality-of-life outcomes from our Phase 3b OPTIC-2 study, while new microbiological results from the Company’s Phase 2 study assessing NUZYRA in NTM-PD will be featured in an oral presentation at IDWeek. We are also pleased that additional, investigator-sponsored studies will provide research findings for NUZYRA in non-respiratory infections, including the treatment of bone and joint infections.” CHEST 2025 Oral Presentation Abstract title: Health-related quality-of-life outcomes in OPTIC-2: A randomized, controlled, Phase 3b trial of omadacycline vs. moxifloxacin in community-acquired bacterial pneumoniaSession: Lung Infections: Considerations in ManagementPresenter: Holly Mallon, RRT, M.S. (Paratek research)Session Date, Time: Tuesday, Oct. 21; 1:45 p.m. - 2:30 p.m. CTSession Location: Lakeside Center Exhibit Hall Rapid Fire Area 1CSession ID: 4043(The study has been supported in whole or part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA) under contract number 75A50120C00001.) CHEST 2025 Poster Session Poster title: Omadacycline outcomes in community-acquired bacterial pneumonia: pooled efficacy and safety from the Phase 3 OPTIC and OPTIC-2 trialsPoster Session Title: Chest Infections Scientific Abstract Posters (F)Presenter: Alex Winans, Pharm.D. (Paratek research)Date, Time: Wednesday, Oct. 22; 10:20 a.m. - 11:05 a.m. CTLocation: Lakeside Center Exhibit Hall Poster Area 1Poster ID: 4101(The study has been supported in whole or part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA) under contract number 75A50120C00001.) IDWeek 2025 Oral Presentation Abstract title: Microbiological Outcomes of Oral Omadacycline Treatment in Adults with Nontuberculous Mycobacterial Pulmonary Disease (NTM-PD) Caused by Mycobacterium abscessus complex (MABc): Results from a Phase 2, Double-blind, Randomized, Placebo-controlled, Multi-center TrialSession: TB and Beyond: Innovations in Treatment, Resistance and Real-World ReachPresenter: Reeti Khare, Ph.D., (Paratek research)Session Date, Time: Tuesday, Oct. 21; 10:30 a.m. - 11:45 a.m. ETSession Location: B207-B208Session ID: 119 IDWeek 2025 Poster Sessions Poster title: Omadacycline was Shown to Preserve the Microbiome in a Murine Model of Post-Influenza MRSA PneumoniaPoster session: Basic Science and Translational StudiesPresenter: Jessica V. Pierce, Ph.D. (Paratek research)Date, Time: Wednesday, Oct. 22; 12:15 p.m. - 1:30 p.m. ETLocation: Poster Hall B4-B5Poster ID: P-1535 Poster title: Pooled Microbiological Outcomes from the Phase 3, Randomized OPTIC and OPTIC-2 Trials of Omadacycline vs Moxifloxacin in Community-acquired Bacterial PneumoniaPoster session: Respiratory infections: Viral and BacterialPresenter: Diane M. Anastasiou, B.S. (Paratek research)Date, Time: Monday, Oct. 20; 12:15 p.m. - 1:30 p.m. ETLocation: Poster Hall B4-B5Poster ID: P-618(The study has been supported in whole or part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA) under contract number 75A50120C00001.) Poster title: In Vitro Activity of Omadacycline and Comparator Agents Against Periodontal PathogensPoster session: Novel AgentsPresenter: David A. Hufnagel, Ph.D. (Investigator-initiated research)Date, Time: Tuesday, Oct. 21; 12:15 p.m. - 1:30 p.m. ETLocation: Poster Hall B4-B5Poster ID: P-1182 Poster title: Susceptibility of Omadacycline in Bone and Joint Infections: Pathogen Susceptibility and Regimen Decisions from an Ongoing Randomized Controlled TrialPoster session: Bone and JointPresenter: Amy Y. Kang, Pharm.D., BCIDP (Investigator-initiated research)Date, Time: Monday, Oct. 20; 12:15 p.m. - 1:30 p.m. ETLocation: Poster Hall B4-B5Poster ID: P-78 About Paratek Pharmaceuticals, Inc. Paratek Pharmaceuticals, Inc. is a privately held pharmaceutical company providing innovative specialty therapies for specialists and community care providers, addressing public health threats and important unmet medical needs. NUZYRA (omadacycline) is a once-daily oral and intravenous antibiotic indicated for adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). XHANCE (fluticasone propionate) is a drug-device combination product indicated for chronic rhinosinusitis (CRS) with or without polyps, targeting the site of inflammation using the proprietary Exhalation Delivery System™ (EDS®). Paratek continues to diversify its portfolio to address unmet patient needs. Paratek was acquired in 2023 by B-FLEXION and Novo Holdings. In December 2019, BARDA awarded Paratek a contract (75A50120C00001) that is now valued at up to approximately $304 million. In addition to supporting the development of NUZYRA for both the treatment and prophylaxis of pulmonary anthrax, this contract supports the U.S. onshoring of NUZYRA and manufacturing security requirements; FDA post-marketing requirements associated with the initial NUZYRA approval; and the procurement of up to 10,000 treatment courses of NUZYRA for the treatment of anthrax. For more information, visit https://www.paratekpharma.com/ or follow us on LinkedIn and X. About NUZYRANUZYRA (omadacycline) is an antibiotic with both once-daily oral and intravenous (IV) formulations indicated for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible microorganisms. A next-generation tetracycline, NUZYRA is specifically designed to overcome tetracycline resistance and exhibits activity across a spectrum of bacteria, including Gram-positive, Gram-negative, atypical, and other drug-resistant strains. IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONS NUZYRA is contraindicated in patients with known hypersensitivity to omadacycline or tetracycline class antibacterial drugs, or to any of the excipients. WARNINGS AND PRECAUTIONS Mortality imbalance was observed in the CABP clinical trial, with eight deaths (2%) occurring in patients treated with NUZYRA compared to four deaths (1%) in patients treated with moxifloxacin. The cause of the mortality imbalance has not been established. All deaths, in both treatment arms, occurred in patients >65 years of age; most patients had multiple comorbidities. The causes of death varied and included worsening and/or complications of infection and underlying conditions. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality. The use of NUZYRA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. The use of NUZYRA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. Hypersensitivity reactions have been reported with NUZYRA. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with other tetracycline class antibacterial drugs. NUZYRA is structurally similar to other tetracycline class antibacterial drugs and is contraindicated in patients with known hypersensitivity to tetracycline class antibacterial drugs. Discontinue NUZYRA if an allergic reaction occurs. Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. NUZYRA is structurally similar to tetracycline class antibacterial drugs and may have similar adverse reactions. Adverse reactions, including photosensitivity, fixed drug eruption, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests), have been reported for other tetracycline class antibacterial drugs, and may occur with NUZYRA. Discontinue NUZYRA if any of these adverse reactions are suspected. Prescribing NUZYRA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions (incidence ≥2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation. DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while taking NUZYRA. Absorption of tetracyclines, including NUZYRA, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended during treatment with NUZYRA. See full prescribing information here. About XHANCEXHANCE is a drug-device combination product that uses the Exhalation Delivery System™ (also known as the EDS®) designed to deliver a topical steroid to the high and deep regions of the nasal cavity where sinuses ventilate and drain. XHANCE is approved by the U.S. Food and Drug Administration for both the treatment of chronic rhinosinusitis without nasal polyps (also called chronic sinusitis) and chronic rhinosinusitis with nasal polyps (also called nasal polyps) in patients 18 years of age or older. IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONS: Hypersensitivity to any ingredient in XHANCE.WARNINGS AND PRECAUTIONS: Local nasal adverse reactions, including epistaxis, erosion, ulceration, septal perforation, Candida albicans infection, and impaired wound healing, can occur. Monitor patients periodically for signs of possible changes on the nasal mucosa. Avoid use in patients with recent nasal ulcerations, nasal surgery, or nasal trauma until healing has occurred.Glaucoma and cataracts may occur with long-term use. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use XHANCE long-term.Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, rash, hypotension, and bronchospasm) have been reported after administration of fluticasone propionate. Discontinue XHANCE if such reactions occur.Immunosuppression and infections can occur, including potential increased susceptibility to or worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients.Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue XHANCE slowly.Assess for decrease in bone mineral density initially and periodically thereafter. ADVERSE REACTIONS: Chronic rhinosinusitis without nasal polyps: The most common adverse reactions (incidence 3%) are epistaxis, headache, and nasopharyngitis.Chronic rhinosinusitis with nasal polyps: The most common adverse reactions (incidence 3%) are epistaxis, nasal septal ulceration, nasopharyngitis, nasal mucosal erythema, nasal mucosal ulcerations, nasal congestion, acute sinusitis, nasal septal erythema, headache, and pharyngitis. DRUG INTERACTIONS: Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS: Hepatic impairment. Monitor patients for signs of increased drug exposure. See full prescribing information here. MEDIA CONTACT: Adam Silversteinadam@scientpr.com

引言 在生命的宏大交响曲中，基因是谱写一切旋律的音符。然而，长久以来，我们对这些音符的控制，似乎还停留在“开”与“关”的简单逻辑上，就像老式收音机上那个只能按下或弹起的开关。我们能让一个基因表达，也能让它沉默。但是，生命过程的精细与复杂，远非这样非黑即白的逻辑所能概括。真正的生命乐章，不仅在于音符的“有”或“无”，更在于其音量的“强”与“弱”。一个基因应该表达多少？是低声吟唱，还是高亢激昂？这种对表达“剂量 (dosage)”的精确控制，是合成生物学、基因与细胞治疗领域亟待突破的核心瓶颈。 想象一下，在细胞重编程或癌症治疗中，如果关键基因的表达“音量”过高，可能导致细胞毒性或脱靶效应；如果“音量”太低，则可能收效甚微。传统的诱导系统，就像一个不太灵敏的音量旋钮，轻轻一拧，结果往往不是所有细胞都发出微弱的声音，而是一部分细胞依旧沉默，另一部分细胞则突然声嘶力竭。这种在细胞群体中表现出的“你有我没”的两极分化，即“双峰分布 (bimodal distribution)”，让精准调控变得遥不可及。 10月13日，《Nature Biotechnology》的研究报道“Programmable promoter editing for precise control of transgene expression”，为我们带来了全新的答案。研究团队开发了一套名为 DIAL (Dial-in Editable Promoters，可调谐可编辑启动子) 的创新框架。这套系统不再是一个简单的开关，更像是一个拥有预设档位的精密“变速箱”，能够对转基因的表达水平进行可编程、可遗传且高度稳定的精细设定，实现了从“开关”到“档位”的跨越。这不仅仅是一项技术革新，更可能为我们理解和驾驭生命过程的方式带来一场深刻的变革。 音量旋钮的困境：为何精准控制如此之难？ 在深入了解DIAL系统的巧妙之前，我们先来看看它所要解决的那个根本性难题：基因表达的剂量敏感性 (dosage-sensitivity)。在发育生物学中，微管蛋白的量稍有偏差，就可能导致神经系统发育异常；在肿瘤学里，一个原癌基因的表达水平是维持正常细胞功能还是走向癌变深渊，往往只有一线之隔。生命对“量”的计较，远比我们想象的要苛刻。 然而，现有的工具箱却显得有些力不从心。最常用的策略是利用化学诱导物，比如四环素 (tetracycline) 或多西环素 (doxycycline)，通过调节诱导物的浓度来控制转录激活蛋白的水平，进而调控下游基因的表达。理论上，这是一个完美的“模拟信号”调控方案。但在现实中，细胞内的分子世界充满了随机性和“噪音”。由于质粒转染效率、蛋白质表达的随机波动等因素，不同细胞内的转录激活蛋白水平参差不齐。 这就导致了一个尴尬的局面：当我们试图通过降低诱导物浓度来实现“低表达”时，系统并不会听话地让所有细胞都进入“低音量”模式。相反，由于激活蛋白在很多细胞中低于启动表达所需的阈值，这些细胞干脆保持沉默 (OFF)；而在少数激活蛋白浓度恰好越过阈值的细胞里，表达一旦开启，便会达到一个较高的水平 (ON)。最终，我们在流式细胞仪上看到的，便是一个分裂成两半的细胞群体：一个“沉默的大多数”和一个“喧哗的少数派”。这种“双峰”现象，是实现均一、可预测调控的巨大障碍，它让基于群体平均水平的实验结论变得不可靠，更让需要全体细胞协同响应的治疗方案举步维艰。 我们需要一种新的设计哲学：一种能够将“表达水平的设定”与“表达水平的波动”解耦的系统。我们需要一个能为所有细胞设定同一个“音量档位”的机制，而不是一个反应迟钝、容易跑偏的旋钮。这正是DIAL系统登场的舞台。DIAL的首次亮相：一把基因剪刀与一个可移动的信号放大器 DIAL系统的核心思想，源于一个对基因转录基本原理的深刻洞察：转录因子 (transcription factor) 结合位点与核心启动子 (core promoter) 之间的物理距离，会显著影响转录效率。距离越近，激活效果越强。DIAL巧妙地将这一原理转化为一个可编程的分子机器。 让我们来拆解一下这个系统的三大核心组件： 1. 合成锌指激活蛋白 (Synthetic Zinc Finger activator, ZFa)：这是一个“信号放大器”。它由两部分构成：一部分是锌指结构域，能够特异性地识别并结合到启动子上的一段特定DNA序列；另一部分是转录激活结构域 (transactivation domain, TAD)，负责招募细胞内的转录机器，启动基因表达。 2. 可切除的间隔序列 (Spacer)：这是一段被精确设计的DNA序列，位于ZFa结合位点和核心启动子之间，扮演着“可变电阻”的角色。它的两端分别被安上了一对特殊的“分子路标”——比如，最常用的 loxP位点。 3. 重组酶 (Recombinase)：这是一把“基因剪刀”，例如 Cre重组酶。Cre能够特异性地识别loxP位点，并精准地切除两个loxP位点之间的DNA序列。 这三个组件如何协同工作？研究人员设计了一个包含 203个碱基对 (bp) 间隔序列的DIAL启动子，并在HEK293T细胞中进行了验证。其逻辑非常清晰： • OFF档 (关闭)：在没有ZFa的情况下，无论间隔序列是否存在，启动子都处于沉默状态，几乎没有基因表达。 • LOW档 (低速)：当细胞内表达ZFa时，它会结合到启动子上。但由于间隔序列的存在，ZFa与核心启动子之间隔着203 bp的距离，这削弱了它的激活能力。此时，系统进入一个稳定的“低表达”状态。 • HIGH档 (高速)：如果在表达ZFa的同时，引入Cre重组酶，神奇的事情发生了。Cre酶会找到间隔序列两端的loxP位点，手起刀落，将这段203 bp的DNA永久性地从基因组上切除。ZFa结合位点与核心启动子的距离瞬间从原来的 316 bp缩短至79 bp。物理距离的拉近，极大地增强了ZFa的激活效率，系统随之切换到一个稳定的“高表达”状态。 通过流式细胞术检测，研究人员证实，这三种输入组合（无ZFa、仅ZFa、ZFa+Cre）确实产生了三个截然不同且高度均一的表达水平。最关键的是，每一个表达水平都呈现出清晰的 “单峰分布 (unimodal distribution)”。这意味着，在特定档位下，几乎所有细胞都表现出相似的表达强度，彻底告别了恼人的“双峰”问题。荧光显微镜下的图像也直观地展示了这一点：在“高档”条件下，视野中的细胞呈现出明亮而均匀的绿色荧光，而在“低档”条件下，则是柔和而均一的微光。从简单开关到复杂调音台：DIAL系统的“自定义”潜力 如果DIAL仅仅能提供三个固定的档位，那它已经足够出色。但它的真正魅力在于其惊人的“可编程性”和“模块化”特性，使其远不止一个三档开关，更像一个可以自定义参数的专业调音台。 1. 自由调节“档位”间距 研究人员猜想，既然间隔序列的长度决定了“低档”的表达水平，那么改变它的长度，是否就能调节“低档”和“高档”之间的差异（fold-change）？他们构建了一系列含有不同长度间隔序列（从27 bp到263 bp）的DIAL启动子。 实验结果与预期完全一致：间隔序列越长，ZFa与核心启动子的距离就越远，导致切除前的“低档”表达水平越低。当Cre酶切除间隔序列后，所有启动子的“高档”表达水平均趋于一致（因为最终的结构是相同的）。这意味着，通过简单地改变间隔序列的长度，研究人员就可以精确地“编程”系统的动态范围。一个长间隔序列的DIAL系统，可以实现一个非常低的初始表达和一个巨大的激活倍数，而一个短间隔序列的系统则提供了一个较高的初始表达和较温和的激活。 2. 更换“放大器”功率 DIAL系统的另一个可调参数是信号放大器ZFa本身。研究人员将结合了不同强度转录激活域（如VP64、VPR）的ZFa与DIAL系统组合。结果显示，使用更强的激活域，不仅能全面提升“低档”和“高档”的表达水平，还能显著增大两者之间的变化差异。例如，使用最强的VPR激活域，其激活倍数超过了22倍，远高于标准VP16激活域的约6倍。这就像给调音台换上了一个功率更强的放大器，整体音量和动态范围都得到了提升。 3. “嵌套”设计实现四档变速 最巧妙的设计之一，是“嵌套式DIAL (nested DIAL)”的提出。研究人员在一个标准的被loxP位点包围的间隔序列内部，又嵌入了一个由另一对正交的重组酶位点，VloxP，所包围的更短的间隔序列。与VloxP位点匹配的“基因剪刀”是 VCre重组酶。 这个精巧的“嵌套”结构，像俄罗斯套娃一样，创造出了四个可编程的稳定状态： • OFF档：无ZFa。 • LOW档：有ZFa，但无任何重组酶。 • MEDIUM档：有ZFa，并加入VCre。VCre只识别VloxP位点，切除内部较短的间隔，使表达水平提升至“中档”。 • HIGH档：有ZFa，并加入Cre。Cre识别外层的loxP位点，将整个间隔序列（包括内部的VloxP结构）全部切除，使表达达到“高档”。 通过这种组合逻辑，仅仅利用一个启动子序列，研究人员就实现了四个跨越一个数量级的稳定表达设定点。这种可扩展性，为构建更复杂的基因表达提供了前所未有的可能。稳定的艺术：DIAL系统如何“无视”细胞噪音？ DIAL系统最深刻、最具变革性的一个特性，在于其对细胞内“噪音”的超强稳健性 (robustness)。如前所述，传统诱导系统最大的痛点，就是其输出对诱导物或转录激活蛋白的浓度极为敏感。而DIAL系统，在特定条件下，能够神奇地“屏蔽”这种敏感性。 研究人员通过两种独立的实验方法，系统地探究了DIAL系统对ZFa表达水平变化的响应。第一种方法是“质粒滴定”，即在转染时使用不同剂量的ZFa表达质粒。第二种方法是使用不同强度的组成型启动子来驱动ZFa的表达。 两种方法都指向了同一个惊人的结论：DIAL系统的响应曲线存在一个“拐点”。在ZFa浓度较低时，DIAL的输出确实随着ZFa的增加而增加，并呈现出双峰分布，这与传统系统类似。然而，一旦ZFa的表达水平超过一个特定的阈值，DIAL的输出便进入了一个 “剂量不敏感 (dosage-invariant)” 的平台期。在这个区间内，即便ZFa的浓度再增加十倍，输出基因的表达水平均保持恒定，并且呈现完美的单峰分布。 这背后的原理可能是启动子饱和 (promoter saturation)。当ZFa足够多时，启动子上所有的结合位点都被占据，系统达到了其最大转录潜能。此时，细胞内ZFa浓度的进一步波动，已无法再影响输出。 这个特性至关重要。它意味着，只要我们确保ZFa的表达水平足够高，使其工作在“剂量不敏感”区间，DIAL系统就能提供一个极其稳定的输出平台。而Cre重组酶的作用，不是在这个敏感的曲线上滑动，而是直接将整个稳定的“平台”向上或向下移动一个台阶。这种设计，巧妙地将“设定档位”这一操作，与细胞内固有的表达噪音隔离开来，确保了输出的稳定性和可预测性。短暂的指令，永恒的记忆：DIAL的可遗传性 DIAL系统的另一个核心优势在于其“记忆”功能。由于Cre重组酶对启动子的编辑是DNA水平上的永久性改变（间隔序列一旦被切除，就无法复原），这意味着一个短暂的外部信号，可以触发一个长期、稳定且可遗传的状态变化。 为了验证这一点，研究人员将DIAL系统通过慢病毒整合到HEK293T细胞的基因组中，构建了一个稳定的细胞系。然后，他们不再使用质粒共转染的方式，而是通过递送编码Cre重组酶的修饰信使RNA (modRNA) 来触发状态切换。modRNA是一种瞬时表达工具，它在细胞内翻译出Cre蛋白后，会在一两天内被降解，信号随之消失。 实验结果显示，接受了Cre modRNA的细胞，其报告基因的表达水平在72小时内稳定地上升到“高档”状态。研究人员对这些细胞进行了长达14天的连续传代培养。结果发现，即便在瞬时的Cre信号消失了近两周后，这些细胞及其后代依然牢牢地维持在“高档”表达水平，与未接受Cre modRNA的对照组之间保持着清晰的界限。这有力地证明了DIAL设定的档位是可遗传的，能够随着细胞分裂稳定地传递给子代。 有趣的是，研究人员还观察到一个细微的现象：处于“高档”表达的细胞，其增殖速度似乎略低于“低档”细胞。这暗示了高水平的外源基因表达可能会给细胞带来一定的代谢负担 (burden)。DIAL系统为研究这类由基因剂量引起的微妙生理效应，提供了一个理想的、高度可控的平台。DIAL在真实生物学场景中的强大应用 一个优秀的合成生物学工具，不仅要在模型细胞（如HEK293T）中表现优异，更要能在更复杂的、与疾病和治疗相关的细胞类型中发挥作用。研究团队在多个维度上展示了DIAL系统的广泛适用性。 首先，该系统具有出色的 “可移植性 (portability)”。研究人员成功地将DIAL系统应用于原代小鼠胚胎成纤维细胞 (MEFs) 和人类诱导多能干细胞 (iPSCs) 中，在这些更“挑剔”的细胞里，DIAL同样能够生成稳定、可控的表达档位。 其次，DIAL框架是 “可扩展的 (extensible)”。研究人员将其与经典的 Tet-On诱导系统 相结合，创造了 TET-DIAL。在这个“混合动力”系统中，小分子药物多西环素 (DOX) 充当了总开关，负责控制系统的“ON/OFF”；而Cre重组酶则负责设定“ON”状态下的具体档位是“Low-ON”还是“High-ON”。这套组合拳兼具了可逆调控（通过添加或移除DOX）和永久档位设定（通过瞬时添加Cre）的优点，大大增强了系统的灵活性。 而最激动人心的，无疑是DIAL系统在模拟真实生物学过程中的应用： 调控细胞命运的直接重编程。研究人员选择了一个经典的细胞命运转变模型：将成纤维细胞直接转化为诱导运动神经元 (induced motor neurons, iMNs)。这个过程受到一个关键信号通路，MAPK通路，的调控，其核心分子 HRas 的一个激活突变体 (HRasG12V) 已被证明是这一过程的正向调节因子。但HRasG12V的最佳表达剂量是多少？过高或过低会有什么影响？ 这正是DIAL大显身手的绝佳场景。研究人员构建了一个由DIAL系统控制HRasG12V表达的慢病毒，并将其导入到MEFs中。通过组合使用ZFa和Cre，他们精确地在细胞中设定了三个HRasG12V的表达水平：OFF、LOW和HIGH。 实验结果清晰地描绘出了一条剂量-效应曲线。 在14天后检测iMN的转化效率，OFF组 几乎没有转化。LOW组 表现出了一定程度的转化。而 HIGH组 的转化效率则显著高于LOW组。由于这三组细胞来源于同一批病毒感染，唯一的变量就是DIAL系统设定的HRasG12V表达档位，这为“更高剂量的HRasG12V能更有效地促进细胞向运动神经元转化”这一结论，提供了强有力的证据。 不仅如此，利用TET-DIAL系统，研究人员还进一步探究了HRasG12V表达的“时间”和“剂量”如何共同影响细胞命运。他们发现，在“高档”表达水平下，一个中等时长的瞬时脉冲（例如，诱导表达7天），其转化效率几乎与持续14天的长脉冲相当。这揭示了细胞命运转变过程中可能存在的“时间窗口”效应，即在关键时期给予足够强度的信号，可能比长期微弱的信号更为有效。重塑基因调控的未来版图 DIAL系统的问世，为合成生物学和基因工程领域提供了一套全新的设计理念和强大的工具。它通过巧妙地利用DNA编辑实现启动子重构，成功地将基因表达的“剂量设定”与细胞内外的“噪音干扰”分离开来。它所提供的可编程、均一、稳定且可遗传的表达档位，解决了传统诱导系统长期以来面临的“双峰”和“不均一”的痛点。 回顾DIAL的设计，它不再是一个简单的模拟“调光器”，而是一个数字化的“档位选择器”，拥有清晰、可靠、可记忆的预设状态。这种模式的转变，意味着我们对基因线路的设计将变得更加“数字化”和可预测，从而大大提高复杂基因线路的性能和成功率。 这项工作也为我们留下了广阔的想象空间。未来，DIAL框架是否可以集成更多的正交重组酶系统，从而实现拥有十几个甚至更多档位的“超级变速箱”？我们是否可以将内源性转录因子的结合位点整合到DIAL中，构建出能够响应细胞自身状态、并能“锁定”响应强度的智能启动子？ 在细胞治疗领域，DIAL或许能为CAR-T等疗法提供更精细的安全控制。通过设定治疗性蛋白的多个表达档位，我们或许可以在确保疗效的同时，将副作用控制在最低水平。在基础研究中，DIAL将成为剖析剂量敏感性基因网络、绘制精细“表型-剂量”图谱的利器。 生命之歌的演奏，终将告别粗糙的“开”与“关”。以DIAL为代表的精准调控工具，正将指挥棒交到我们手中，让我们有机会以前所未有的精度，去谱写、去编辑、去微调那些决定细胞命运与功能的生命乐章。一个基因表达可被精确编程的时代，已然拉开序幕。 参考文献 Kabaria SR, Bae Y, Ehmann ME, Lende-Dorn BA, Beitz AM, Peterman EL, Love KS, Ploessl DS, Galloway KE. Programmable promoter editing for precise control of transgene expression. Nat Biotechnol. 2025 Oct 13. doi: 10.1038/s41587-025-02854-y. Epub ahead of print. PMID: 41083901. 声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！ 往期热文： Science | 解构生命编码的“折叠时空”：一次颠覆教科书的剪接新发现 Science | 生存的两种“投资学”：伪装是机会主义套利，警戒色是长期价值投资？ Nature | 饮食为“矛”，药物为“盾”：协同耗竭多胺，重编程神经母细胞瘤的增殖与分化程序 Science | 我们继承的，不止是基因：溶酶体如何将“长寿祝福”遗传给后代？ Nature | 掌控生命节拍：为蛋白质装上“秒级”开关 Cell | 癌症的“甜蜜陷阱”：用“魔术贴”粘住肿瘤，新一代免疫疗法GlyTR横空出世