Quaratusugene ozeplasmid

脂质体（Liposome）是一种由磷脂等两性分子自发形成的封闭囊泡结构，随着纳米技术、材料科学等多学科的交叉发展，脂质体的研究与应用进入了一个新的阶段，并在肿瘤研究、疫苗研发、基因递送等多个领域发挥着关键作用。 一 脂质体的基本结构  脂质体的基本结构是由磷脂分子在水相中自发聚集形成的双分子层结构。磷脂分子具有亲水的头部和疏水的尾部，亲水头部朝向外部水相，而疏水尾部相互靠近形成内部疏水区域。这种结构使得脂质体的内部能够包裹水溶性活性物，同时也能将脂溶性物质嵌入双分子层中。 二 合成脂质体的关键组分 合成脂质体的关键组分主要包括天然或合成的脂质、多糖、固醇以及表面活性剂。 图1. 合成脂质体的主要材料[1] 1. 合成脂质 合成脂质，即非天然存在或来源于化学合成的脂质，它们在生物学和结构上与天然脂质相似，具有高生物相容性和较高的纯度。合成脂质常用于构建各种响应性或具有其它特殊功能的脂质体（例如温敏性脂质体），以及用于构建DNA/RNA相关的转染和递送载体。 DLin-MC3-DMA  DLin-MC3-DMA （MC-3，RV-28）是一种可电离的阳离子脂质。其结构特点如下：其头部含有1个叔胺基团（pKa≈6.5），在生理pH下呈中性，在酸性内体环境中质子化带正电；尾部包含两个由亚油酸组成的疏水长链，具有较强的膜融合能力；在头尾部之间是一个由短碳链（C3）组成的连接基团，用于平衡亲疏水性质。DLin-MC3-DMA是一种siRNA的高效载体，对多种细胞均具有较高的转染效率。此外，DLin-MC3-DMA还可用于mRNA疫苗的负载和在动物体内的递送。 SM-102 SM-102是一种可电离的阳离子脂质，广泛应用于脂质体，特别是核酸及mRNA疫苗递送相关脂质体的合成。SM-102的结构由亲水且带正电荷的头部、连接基团和一个疏水的尾部组成。其头部在酸性环境中可以质子化，形成正电荷，从而与带负电荷的核酸（如mRNA）通过静电作用结合。此外，SM-102在脂质纳米颗粒中能够引起内涵体膜不稳定，有助于脂质纳米颗粒从内涵体中逃逸，从而提高药物或基因的递送效率。 C12-200 C12-200是一种在生物医学研究领域有重要用途的可电离阳离子类脂质和辅助脂质。C12-200是一种高效的mRNA运输载体，能有效封装相应的mRNA并使其进入细胞质内，C12-200还可用于合成脂质纳米颗粒，并作为siRNA或CRISPR的递送系统。 ALC-0159 ALC-0159是一种PEG化的脂质赋形剂，广泛应用于脂质体的合成，尤其是在mRNA疫苗的研发中。ALC-0159自带的PEG链能够显著增加纳米粒子在体内的循环时间。通过PEG化修饰可以减少脂质体的蛋白质吸附，减少免疫系统对纳米粒子的识别和清除。ALC-0159的存在可以减少纳米颗粒表面的免疫原性，这种特性使得ALC-0159在mRNA疫苗的递送中表现出色。 Surfactin Surfactin（表面活性素）是一种由枯草芽孢杆菌（Bacillus subtilis）产生的环状脂肽类表面活性剂，Surfactin具有很强的表面活性，能够降低脂质体表面的张力，从而增强脂质体的稳定性。其环状结构和亲水性头部使其能够嵌入脂质体的磷脂双层中，形成稳定的界面。 DOTAP（1,2-二油酰基-sn-甘油-3-三甲基铵丙烷） DOTAP（1,2-Dioleoyl-3-trimethylammonium-propane）是一种阳离子脂质，其带的正电荷由分子结构中的三甲基氨基团提供。DOTAP的正电荷使其能够与带负电荷的DNA或RNA形成复合物，保护核酸免受核酸酶的降解，并通过内吞作用被细胞摄取，从而实现基因的高效转染。 DPPC（二棕榈酰磷脂酰胆碱） DPPC（1,2-Dipalmitoyl-sn-glycero-3-phosphocholine）具有较高的相变温度（41℃），在低于相变温度时，它以液晶凝胶相存在，分子排列较为紧密；当温度升高至相变温度以上时，转变为液晶相，分子的流动性增加。基于以上特性，DPPC常被用于构建温敏性脂质体。 DOPC（1,2-二油酰基-sn-甘油-3-磷脂酰胆碱） DOPC（1,2-Dioleoyl-sn-glycero-3-phosphocholine）属于磷脂酰胆碱类化合物，其分子结构由一个胆碱基团、一个磷酸基团、一个甘油骨架以及两条油酰基脂肪酸链组成。DOPC中的不饱和脂肪酸链（油酰基）使得脂质体在生理温度下保持较高的流动性。DOPC可以与阳离子脂质（如DOTAP）混合，形成复合物，用于基因转染。 DSPC（1,2-二硬脂酰基-sn-甘油-3-磷脂酰胆碱） DSPC（1,2-Distearoyl-sn-glycero-3-phosphorylcholine）具有长的饱和脂肪链，可形成稳定的脂双层结构并提高脂质体的稳定性。DSPC的脂肪酸链比DPPC长，这使得DSPC的分子更大，相变温度更高。DSPC广泛用于mRNA疫苗的载体，具有较长的体内半衰期。 DOPE（1,2-二油酰基-sn-甘油-3-磷脂酰乙醇胺） DOPE（1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine）的脂肪酸链是不饱和的（含有双键），这使得DOPE的分子更灵活，相变温度更低。DOPE更适合用于构建需要高流动性的脂质体递送载体，如基因转染。 DLinDMA（1,2-二油酰基-3-二甲基氨基丙烷） DLinDMA（ 1,2-dilinoleyloxy-3-dimethylaminopropane）是一种可电离的阳离子脂质，其结构可以分为三个主要区域：疏水的烃链、连接链和头部基团，其结构中包含一个可质子化的叔胺基团。由DLinDMA合成的脂质体可用于siRNA递送。此外，DLinDMA广泛用于多种脂质体纳米颗粒的构建，并作为递送载体，在mRNA疫苗、基因、化合物等生物活性物质的递送等领域表现出重要的应用前景。 CKK-E12  CKK-E12是一种新型的脂质材料，具有良好的生物相容性和稳定性。CKK-E12的分子结构包含两个油酸链（C18:1）和一个可质子化的叔胺头部。CKK-E12具有可电离的性质，常与其他脂质结合构成脂质纳米颗粒。CKK-E12具有 pH 敏感性，在低 pH 值下带正电，有较强的核酸结合能力，而在血液 pH 值（pH7.4）下大部分不带电，因此具有较长的循环时间。此外，CKK-E12 在体内实验中对肝细胞具有高度选择性，因此在肝脏研究中具有独特优势。 DOTMA DOTMA（N,N-Dioleoyl-N,N-dimethylamidinium）也是一种阳离子脂质，可用于封装多种核苷酸分子，并用于体外基因转染。DOTMA 通过自身携带的正电荷，促进脂质体与细胞膜的有效相互作用。含有DOTMA的脂质体具有良好的膜融合特性，能够与细胞膜高效融合，将包裹的分子释放到细胞内部。 2. 天然脂质和其他天然组分 在实验中常用于合成脂质体的天然组分主要有磷脂、鞘脂、甾醇、多糖、固醇等几个大类。 磷脂  天然磷脂是动物细胞膜中最常见的组分之一，也是合成脂质体的核心成分。常用于合成脂质体的天然磷脂主要包括卵磷脂（Phosphatidylcholine，PC）、磷脂酰肌醇（Phosphatidylinositol, PI）、磷脂酰乙醇胺（Phosphatidylethanolamine，PE）等[2]。上述天然磷脂可以经过进一步修饰，进而具有更好的稳定性或其他特性，例如，磷脂酰乙醇胺（PE）通常通过胺基与聚乙二醇缀合以增加脂质体的生物相容性，保持稳定性。 甾醇 甾醇有三种亚型：植物甾醇、动物甾醇和真菌甾醇，它们分别存在于植物、动物和微生物中。胆固醇是一种内源性两亲性动物甾醇，是哺乳动物细胞膜的重要组成部分。在细胞膜内，胆固醇（Cholesterol）主要存在于脂筏中，它在调节膜完整性和脂筏功能的过程中发挥重要作用[3]。脂质体制剂中胆固醇的掺入已被证明可增加体内稳定性并降低了脂质双层的泄漏。与缺乏胆固醇的对照组相比，脂质体制剂中加入20%-50%的胆固醇后，体内稳定性增加[4, 5]。除此之外，提取自酵母细胞中的麦角甾醇（Ergosterol）可用作胆固醇的替代品，尤其是在需要避免动物来源成分的情况下，它能够调节脂质体膜的流动性和稳定性[4]。 多糖 多糖在细胞通讯中发挥着重要作用，它们存在于细胞膜中，参与细胞和组织的识别过程以及某些转运机制。用寡糖或多糖包被脂质膜可以将脂质体靶向特殊的细胞受体或延长体内循环。多糖具有额外的特性，使其非常适合用于构建脂质体，例如抗病毒、抗细菌和抗肿瘤特性。脂质体制剂中常用到的多糖是壳聚糖（Chitosan）和透明质酸（Hyaluronic Acid）[6]。 3. 表面活性剂 表面活性剂是一种可降低其所结合的液体的表面张力的分子，是脂质体合成过程中关键的添加剂之一。脂质体合成中较常用到的表面活性剂主要有以下几类：胆酸钠（Cholic acid sodium）、司盘60（Span 600）、和吐温80（Tween 80）。上述表面活性剂常用于对脂质体进行改性，以便脂质体实现对特殊内容物的负载。例如使用具有正电位的胆酸钠与带负电荷的成分（如DNA）结合。表面活性剂的类型和浓度可用于提高脂质体的包封和递送效率[7]。 三 脂质体的主要制备方法 合成脂质体的主要方法有多种，每种方法都有其独特的操作步骤和适用场景。以下是几种常见的脂质体合成方法的概述： 1. 薄膜分散法（Thin Film Hydration） 薄膜分散法是制备脂质体的经典方法。首先，将脂质溶解在有机溶剂（如氯仿或乙醚）中，然后通过旋转蒸发或氮气吹干的方式在容器壁上形成均匀的薄膜。随后，加入适量的水相（如生理盐水或缓冲液）使薄膜水化，形成多层脂质体。为了获得更小且均匀的脂质体，通常需要进一步的处理，如超声处理或通过微孔膜挤出。 2. 乙醇注入法（Ethanol Injection） 乙醇注入法是一种快速制备脂质体的方法。将脂质溶解在乙醇中，然后将此溶液快速注入到含有水相的搅拌容器中。乙醇的快速扩散导致脂质分子在水相中迅速聚集形成脂质体。此方法的优点是操作简单且无需有机溶剂的蒸发，但需要控制乙醇的注入速度和搅拌条件，以避免脂质体的过度聚集。 3. 逆相蒸发法 （Reverse Phase Evaporation） 逆相蒸发法适用于制备负载水溶性活性物质的脂质体。首先，将脂质溶解在有机溶剂中，然后加入含有要负载的生物活性物质的水相，形成水包油乳液。通过旋转蒸发去除有机溶剂，形成脂质体。此方法的优点是能够将水溶性化合物包载在脂质体的水相中，但操作相对复杂，需要精确控制蒸发条件。 4. 超声法（Ultrasonication） 超声法是通过超声波的机械作用来制备脂质体。将脂质溶解在有机溶剂中，蒸发形成薄膜后，加入水相使薄膜水化。然后，利用超声波的能量使脂质体分散成更小的尺寸。此方法的优点是能够制备较小且均匀的脂质体，但需要注意超声时间和功率，以避免脂质体的破裂。 5. 挤出法（Extrusion） 挤出法是制备均匀脂质体的有效方法。首先，通过薄膜分散法或其他方法制备出粗脂质体，然后将脂质体溶液通过聚碳酸酯膜或其他类型的挤出膜进行挤出。通过多次挤出，可以得到尺寸均一的脂质体。此方法的优点是能够精确控制脂质体的尺寸，适合大规模生产。 参考文献及鸣谢 [1] SPANGLER J B, MORAGA I, MENDOZA J L, et al. Insights into cytokine-receptor interactions from cytokine engineering [J]. Annual review of immunology, 2015, 33: 139-67. [2] ZENG K, XIE W, WANG C, et al. USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma [J]. Cell death & disease, 2023, 14(3): 194. [3] ZHOU Q, LEI Y. ARMCX3 regulates ROS signaling, affects neural differentiation and inflammatory microenvironment in dental pulp stem cells [J]. Heliyon, 2024, 10(17): e37079. [4] TU P, PAN Y, WANG L, et al. CD62E- and ROS-Responsive ETS Improves Cartilage Repair by Inhibiting Endothelial Cell Activation through OPA1-Mediated Mitochondrial Homeostasis [J]. Biomaterials research, 2024, 28: 0006. [5] FU H, ZHANG P, ZHAO X D, et al. Interfering with Rac1-activation during neonatal monocyte-macrophage differentiation influences the inflammatory responses of M1 macrophages [J]. 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Expects to Complete Enrollment of First 25 Patients in Phase 2 Expansion Study During Second Half of 2025 for Interim Analysis Acclaim-3 Study Has FDA Orphan Drug and Fast Track Designations AUSTIN, Texas, Jan. 23, 2025 /PRNewswire/ -- Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, today announced that the first patient has been enrolled and dosed in the Phase 2 expansion portion of the Company's Acclaim-3 clinical study of Reqorsa® Gene Therapy (quaratusugene ozeplasmid) in combination with Tecentriq® (atezolizumab) as maintenance therapy for patients with extensive stage small cell lung cancer (ES-SCLC). "We are excited to begin the Phase 2 expansion portion of Acclaim-3, which will determine the 18-week Progression Free Survival (PFS) rate of REQORSA and Tecentriq combination maintenance therapy," said Mark Berger, MD, Chief Medical Officer at Genprex. "ES-SCLC has a poor prognosis with a median PFS of 5.2 months. Those patients receiving Tecentriq as maintenance therapy have a median PFS of 2.6 months after the start of maintenance therapy. We look forward to studying the combination of REQORSA and Tecentriq as we work to advance our innovative gene therapy." The Phase 2 expansion portion will enroll 50 patients at approximately 10 to 15 U.S. sites. Patients will be treated with REQORSA and Tecentriq until disease progression or unacceptable toxicity is experienced. The primary endpoint of the Phase 2 portion is to determine the 18-week progression-free survival rate from the time of the start of maintenance therapy with REQORSA and Tecentriq in patients with ES-SCLC. Patients will also be followed for survival. A Phase 2 interim analysis will be performed after the 25th patient enrolled and treated reaches 18 weeks of follow up. The Company expects to complete enrollment of the first 25 patients in the second half of 2025 for interim analysis. The combination of REQORSA and Tecentriq previously received the U.S. Food and Drug Administration's (FDA) Fast Track Designation for the treatment of the Acclaim-3 patient population, and the FDA has also granted Orphan Drug Designation to REQORSA for the treatment of SCLC. Genprex has a novel cancer treatment platform that re-expresses tumor suppressor genes in cancers. Tumor suppressor genes are often deleted or inactivated early in the process of cancer development. REQORSA contains a plasmid that expresses TUSC2, a tumor suppressor gene protein. Nearly 100% of SCLCs have reduced or no TUSC2 protein expression, and 41% completely lack TUSC2 protein expression. Nonclinical studies in mice support the hypothesis that re-expressing the TUSC2 protein may lead to improved clinical efficacy in combination with Tecentriq. Data presented at the October 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics from studies in humanized mouse models of SCLC that use human H841 SCLC cells have shown that the combination of REQORSA and Tecentriq provides significantly better control of tumor burden than either agent alone. The data from these studies also suggest that a combination treatment of REQORSA and Tecentriq can promote a significantly increased tumor cell killing effect in SCLC xenografts compared to that of Tecentriq alone. About Acclaim-3 The Acclaim-3 clinical trial is an open-label, multi-center Phase 1/2 clinical trial evaluating the Company's lead drug candidate, Reqorsa® Gene Therapy, in combination with Genentech, Inc.'s Tecentriq® (atezolizumab) as maintenance therapy in patients with extensive stage small cell lung cancer (ES-SCLC) who did not develop tumor progression after receiving Tecentriq and chemotherapy as initial standard treatment. About Genprex, Inc. Genprex, Inc. is a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes. Genprex's technologies are designed to administer disease-fighting genes to provide new therapies for large patient populations with cancer and diabetes who currently have limited treatment options. Genprex works with world-class institutions and collaborators to develop drug candidates to further its pipeline of gene therapies in order to provide novel treatment approaches. Genprex's oncology program utilizes its systemic, non-viral Oncoprex® Delivery System which encapsulates the gene-expressing plasmids using lipid-based nanoparticles in a lipoplex form. The resultant product is administered intravenously, where it is taken up by tumor cells that then express tumor suppressor proteins that were deficient in the tumor. The Company's lead product candidate, Reqorsa® Gene Therapy (quaratusugene ozeplasmid), is being evaluated in two clinical trials as a treatment for NSCLC and SCLC. Each of Genprex's lung cancer clinical programs has received a Fast Track Designation from the FDA for the treatment of that patient population, and Genprex's SCLC program has received an FDA Orphan Drug Designation. Genprex's diabetes gene therapy approach is comprised of a novel infusion process that uses an AAV vector to deliver Pdx1 and MafA genes directly to the pancreas. In models of Type 1 diabetes, GPX-002 transforms alpha cells in the pancreas into functional beta-like cells, which can produce insulin but may be distinct enough from beta cells to evade the body's immune system. In a similar approach, GPX-002 for Type 2 diabetes, where autoimmunity is not at play, is believed to rejuvenate and replenish exhausted beta cells. Interested investors and shareholders are encouraged to sign up for press releases and industry updates by visiting the Company Website, registering for Email Alerts and by following Genprex on Twitter, Facebook and LinkedIn. Cautionary Language Concerning Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are made on the basis of the current beliefs, expectations and assumptions of management, are not guarantees of performance and are subject to significant risks and uncertainty. These forward-looking statements should, therefore, be considered in light of various important factors, including those set forth in Genprex's reports that it files from time to time with the Securities and Exchange Commission and which you should review, including those statements under "Item 1A – Risk Factors" in Genprex's Annual Report on Form 10-K for the year ended December 31, 2023. Because forward-looking statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding: Genprex's ability to advance the clinical development, manufacturing and commercialization of its product candidates in accordance with projected timelines and specifications, such as REQORSA in combination with other therapies in SCLC; the timing and success of Genprex's clinical trials and regulatory approvals, including, but not limited to, the enrollment of the Phase 2 expansion portions of the Acclaim-3 trial; the effect of Genprex's product candidates, alone and in combination with other therapies, on cancer and diabetes; the effects of any strategic research and development prioritization initiatives, and any other strategic alternatives or other efforts that Genprex takes or may take in the future that are aimed at optimizing and re-focusing Genprex's diabetes, oncology and/or other clinical development programs including prioritization of resources, and the extent to which Genprex is able to implement such efforts and initiatives successfully to achieve the desired and intended results thereof; Genprex's future growth and financial status, including Genprex's ability to maintain compliance with the continued listing requirements of The Nasdaq Capital Market and to continue as a going concern and to obtain capital to meet its long-term liquidity needs on acceptable terms, or at all; Genprex's commercial and strategic partnerships, including those with its third party vendors, suppliers and manufacturers and their ability to successfully perform and scale up the manufacture of its product candidates; and Genprex's intellectual property and licenses. These forward-looking statements should not be relied upon as predictions of future events and Genprex cannot assure you that the events or circumstances discussed or reflected in these statements will be achieved or will occur. If such forward-looking statements prove to be inaccurate, the inaccuracy may be material. You should not regard these statements as a representation or warranty by Genprex or any other person that Genprex will achieve its objectives and plans in any specified timeframe, or at all. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. Genprex disclaims any obligation to publicly update or release any revisions to these forward-looking statements, whether as a result of new information, future events or otherwise, after the date of this press release or to reflect the occurrence of unanticipated events, except as required by law. Genprex, Inc. (877) 774-GNPX (4679) GNPX Investor Relations [email protected] GNPX Media Contact Kalyn Dabbs [email protected] SOURCE Genprex, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED