Creating an sxRNA Organoid Product for Advancing the Study, Prevention and Treatment of Alzheimer's disease (AD) and Alzheimer's-disease-related dementias (ADRD)

创建 sxRNA 类器官产品以推进阿尔茨海默病 (AD) 和阿尔茨海默病相关痴呆 (ADRD) 的研究、预防和治疗

• 批准号: 10765970
• 负责人: JANET L PALUH
• 金额: $ 50万
• 依托单位: SXRNA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10765970
• 关键词: 3-Dimensional; Action Potentials; Aftercare; Aging; Alginates; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Binding; Binding Proteins; Binding Sites; Biological Models; Cell Aging; Cell Culture Techniques; Cell Death; Cells; Clinical Trials; Complex; Development; Drug usage; Encapsulated; Engineering; Excision; Failure; Fibrosis; Functional disorder; Ganciclovir; Gene Expression; Genes; Goals; Human; In Vitro; Maps; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular; Nerve Degeneration; Neuroglia; Neuronal Differentiation; Neurons; Organ; Organoids; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiology; Play; Prevention; Process; Proteins; RNA; RNA Binding; Reporter; Reporter Genes; Reporting; Research; Role; Screening procedure; Small Business Technology Transfer Research; Specificity; Spinal cord injury; Standardization; Structure; System; Technology; Testing; Therapeutic; Time; Tissue Model; Tissues; Translating; Translations; Uncertainty; Untranslated RNA; Validation; Visualization; cellular targeting; commercialization; delivery vehicle; design; drug candidate; drug development; genetic manipulation; high throughput screening; high-throughput drug screening; human stem cells; nerve stem cell; neural; neural network; neuroregulation; novel; posttranscriptional; research and development; senescence; stem; stem cells; suicide gene; technology platform; three dimensional cell culture; three-dimensional modeling; tissue culture; tool

Abstract – sxRNA Technologies (sxRNATech) is developing an organoid toolkit for Alzheimer’s Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD) that will enable the identification of senescent cells in living tissue providing a novel tool for studying senescence and how it relates to the aging processes while also creating a new platform for high-throughput drug screening in in complex 3D tissue models. Complex 3D tissue cultures such as ribbons, gastruloids and organoids, which utilize stem cells to re-create organs in vitro, have tremendous potential for commercial and academic research. However, there are still limitations inhibiting their widespread use for AD/ADRD research and drug development, especially with respect to senescent cells. The harmful effects of senescence are attributed to high secretory activity, referred to as the Senescence Associated Secretory Phenotype (SASP), which leads to fibrosis and decline in organ function. Although it is presently unclear whether cellular senescence is a cause or a consequence of neurodegeneration and which comes first, there is little doubt that the two are connected and a better understanding of the role senescence in AD and ADRD is critical. sxRNA Tech is the pioneer of structurally interacting RNA (sxRNA), which is an RNA-based technology that enables the specific mapping and manipulation of gene expression in living cells. sxRNA is based on the binding of one RNA molecule to a second RNA molecule in a manner designed to “switch” the structural confirmation of the first RNA into an active “functional” form. The presence of a selected cellular microRNAs is then used to turn ON the translational activity of an sxRNA engineered mRNA by interacting with it in a manner that creates a new binding site for a protein that regulates translation. The objective of this STTR is to adapt the sxRNA technology, which is well established in traditional plated cell culture, to function as a tool for screening of AD/ADRD drug candidates that limit senescence engagement in complex 3D human-cell cultures that more close recapitulate human physiology and pathophysiology. During this (PhI) STTR project, sxRNA Tech will expand the utility of the sxRNA platform technology for delivery, mapping, and control of senescence in complex 3D tissue models. We will begin by developing an appropriate delivery vehicle for introducing positive control sxRNAs into neural ribbons. We will then use this method to deliver reporter based, switchable SENsxRNAs into ribbons demonstrating expression is restricted to senescent cells, and lastly, use a therapeutic SENsxRNA to selectively eliminate and/or modulate cells from the 3D tissues. This will pave the way for sxRNA Tech commercialization of products that enhance 3D tissue model expansion while increasing standardization, providing new value to customers.

抽象的 - SXRNA Technologies（SXRNATECH）正在为阿尔茨海默氏病（AD）和 阿尔茨海默氏症与疾病相关的痴呆症（ADRD）将使感觉细胞在生活中识别 组织提供了一种新型工具来研究感应及其与衰老过程的关系 在复杂的3D组织模型中创建一个用于高通量药物筛查的新平台。复杂的3D组织 丝带，胃类和器官等培养物，利用干细胞在体外重新创建器官的培养物 商业和学术研究的巨大潜力。但是，仍然存在限制的限制 广泛用于AD/ADRD研究和药物开发，尤其是在感觉细胞方面。 感应的有害作用归因于高分泌活动，称为衰老 秘书表型（SASP），导致器官功能纤维化和下降。虽然目前是 尚不清楚细胞感应是神经退行性的原因还是结果，并且首先是 毫无疑问，这两者是连接的，并且更好地理解了AD中的角色感受和 ADRD至关重要。 SXRNA Tech是结构相互作用RNA（SXRNA）的先驱，这是一种基于RNA的 能够对活细胞中基因表达进行特定的映射和操纵的技术。 sxrna是 基于一个RNA分子与第二个RNA分子的结合，以“切换”的方式 将第一个RNA的结构确认为主动的“功能”形式。选定的细胞的存在 然后，microRNA用于通过与 它以一种为调节翻译的蛋白质创建新的结合位点的方式。这个sttr的目的 是为了适应在传统的镀层细胞培养中已建立的SXRNA技术，以便作为工具 为了筛选限制复杂3D人物衰老参与度的AD/ADRD候选药物 更紧密地概括人类生理学和病理生理学的培养物。在此（phi）sttr项目中， SXRNA Tech将扩大SXRNA平台技术的实用性，用于交付，映射和控制 复杂的3D组织模型中的感应。我们将首先开发适合的送货工具 将阳性对照SXRNA引入神经丝带。然后，我们将使用此方法来提供基于记者的方法， 可切换的Sensxrnas到表达表达的丝带中仅限于感觉细胞，最后，使用 治疗性sensxRNA可选择性地消除和/或调节3D组织中的细胞。这将铺平道路 用于SXRNA技术的产品商业化，以增强3D组织模型扩展同时增加 标准化，为客户提供新价值。