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.

摘要-- sxRNA技术公司（sxRNATech）正在开发一种用于阿尔茨海默病（AD）的类器官工具包， 阿尔茨海默病相关痴呆症（ADRD），这将使衰老细胞的识别在生活中， 组织提供了一种新的工具，用于研究衰老及其与衰老过程的关系， 为复杂的3D组织模型中的高通量药物筛选创造了一个新的平台。复杂三维组织 利用干细胞在体外重建器官的培养物，如带状物、类胃体和类器官， 商业和学术研究的巨大潜力。然而，仍然存在限制其 广泛用于AD/ADRD研究和药物开发，特别是关于衰老细胞。的 衰老的有害影响归因于高分泌活性，称为衰老相关的 分泌型（SASP），导致纤维化和器官功能下降。虽然目前 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，这两者是相关的，更好地理解衰老在AD中的作用， ADRD是关键。sxRNA Tech是结构相互作用RNA（sxRNA）的先驱，这是一种基于RNA的 该技术能够在活细胞中对基因表达进行特异性定位和操作。sxRNA是 基于一种RNA分子与第二种RNA分子的结合，这种结合被设计为“转换”RNA分子的方式。 将第一个RNA结构确认为活性“功能”形式。一个选定的细胞的存在 然后使用microRNA通过与mRNA相互作用来开启sxRNA工程化mRNA的翻译活性。 它以一种为调节翻译的蛋白质创造一个新的结合位点的方式。本STTR的目标是 在传统的平板细胞培养中，sxRNA技术已经得到了很好的应用， 用于筛选AD/ADRD候选药物，其限制复杂的3D人类细胞中的衰老参与 更接近人类生理和病理生理的文化。在本（PhI）STTR项目期间， sxRNA Tech将扩大sxRNA平台技术的实用性，用于递送，映射和控制 复杂3D组织模型中的衰老。我们将开始开发一个适当的运载工具， 将阳性对照sxRNA引入神经带。然后，我们将使用这种方法来提供基于记者， 将SENsxRNA转换成条带，证明表达仅限于衰老细胞，最后，使用 治疗性SENSxRNA以选择性地从3D组织中消除和/或调节细胞。这将铺平道路 对于sxRNA Tech的产品商业化，增强3D组织模型扩展，同时增加 标准化，为客户提供新的价值。