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

摘要- SxRNA Technologies(SxRNATech)正在开发一种治疗阿尔茨海默病(AD)的有机类工具包，并 阿尔茨海默氏症-疾病相关痴呆(ADRD)将能够识别活着的衰老细胞 组织为研究衰老及其与衰老过程的关系提供了新的工具，同时还 在复杂的3D组织模型中创建高通量药物筛选的新平台。复杂的3D组织 利用干细胞在体外重建器官的培养物，如丝带、原肠和类器官，有 商业和学术研究的巨大潜力。然而，仍然有一些限制限制了他们的 广泛用于AD/ADRD研究和药物开发，特别是在衰老细胞方面。这个 衰老的有害影响归因于高分泌活动，称为与衰老相关的 分泌表型(SASP)，导致纤维化和器官功能下降。虽然目前它是 尚不清楚细胞衰老是神经退行性变的原因还是后果，哪一种是第一位的， 毫无疑问，这两者是有联系的，对衰老在AD和AD中的作用有更好的理解 ADRD是至关重要的。SxRNA Tech是结构相互作用RNA(SxRNA)的先驱，它是一种基于RNA的 能够对活细胞中的基因表达进行特定映射和操作的技术。SxRNA是 基于一个RNA分子与另一个RNA分子的结合，其设计方式是将 将第一个RNA结构确认为一种活性的“功能”形式。所选蜂窝的存在 然后，microRNAs被用来通过与sxRNA工程的mrna相互作用来开启其翻译活性。 它的方式是为调节翻译的蛋白质创建一个新的结合位点。本次科技攻关的目标是 是使在传统的平板细胞培养中建立起来的sxrna技术成为一种工具。 用于筛选限制复杂3D人体细胞中衰老参与的AD/ADRD候选药物 更接近人类生理学和病理生理学的培养。在这个(Phi)STTR项目中， SxRNA Tech将扩展sxRNA平台技术的效用，用于交付、映射和控制 复杂3D组织模型中的衰老。我们将首先开发一种适当的递送工具来 将阳性对照sxRNAs引入神经带。然后我们将使用这种方法来传递基于记者的， 可切换成条带的SENsxRNA显示表达仅限于衰老细胞，最后，使用 治疗性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 用于sxRNA技术产品的商业化，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。

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.