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) 正在开发一种用于治疗阿尔茨海默病 (AD) 和 阿尔茨海默病相关痴呆症（ADRD）将能够识别活体中的衰老细胞 组织为研究衰老及其与衰老过程的关系提供了一种新工具，同时也 创建一个在复杂 3D 组织模型中进行高通量药物筛选的新平台。 丝带、类原肠胚和类器官等培养物利用干细胞在体外重建器官， 商业和学术研究的巨大潜力然而，仍然存在限制它们的因素。 广泛用于 AD/ADRD 研究和药物开发，特别是在衰老细胞方面。 衰老的有害影响归因于高分泌活性，称为衰老相关 分泌表型（SASP），导致纤维化和器官功能下降，尽管目前是这样。 尚不清楚细胞衰老是神经退行性变的原因还是结果，以及哪个先发生， 毫无疑问，两者是相关的，并且可以更好地理解衰老在 AD 和 AD 中的作用。 ADRD 至关重要，sxRNA Tech 是结构相互作用 RNA (sxRNA) 的先驱，它是一种基于 RNA 的技术。 能够对活细胞中的基因表达进行特定定位和操作的技术是。 基于一个 RNA 分子与第二个 RNA 分子的结合，其方式旨在“切换” 第一个 RNA 的结构确认为活性“功能”形式 选定细胞的存在。 然后使用 microRNA 通过与 sxRNA 工程改造的 mRNA 相互作用来开启翻译活性 它以一种为调节翻译的蛋白质创建新的结合位点的方式。 是采用传统平板细胞培养中成熟的 sxRNA 技术作为工具 用于筛选限制复杂 3D 人类细胞衰老的 AD/ADRD 候选药物 在这个（PhI）STTR项目中，更接近地概括人类生理学和病理生理学的文化。 sxRNA Tech 将扩展 sxRNA 平台技术在递送、绘图和控制方面的效用 我们将首先开发一种合适的递送载体来研究复杂的 3D 组织模型中的衰老。 然后，我们将使用这种方法来提供基于报告基因的阳性对照 sxRNA。 可将 SENsxRNA 转换成带状，证明表达仅限于衰老细胞，最后，使用 SENsxRNA 选择性地消除和/或调节 3D 组织中的细胞，这将为我们铺平道路。 sxRNA Tech 产品的商业化可增强 3D 组织模型扩展，同时增加 标准化，为客户提供新价值。