sxRNA Technologies (sxRNATech) is developing an organoid toolkit for Alzheimer's Disease (AD) andAlzheimer's-Disease-Related Dementias (ADRD) that will enable the identification of senescent cells in livingtissue providing a novel tool for studying senescence and how it relates to the aging processes while alsocreating a new platform for high-throughput drug screening in in complex 3D tissue models. Complex 3D tissuecultures such as ribbons, gastruloids and organoids, which utilize stem cells to re-create organs in vitro, havetremendous potential for commercial and academic research. However, there are still limitations inhibiting theirwidespread use for AD/ADRD research and drug development, especially with respect to senescent cells. Theharmful effects of senescence are attributed to high secretory activity, referred to as the Senescence AssociatedSecretory Phenotype (SASP), which leads to fibrosis and decline in organ function. Although it is presentlyunclear 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 andADRD is critical. sxRNA Tech is the pioneer of structurally interacting RNA (sxRNA), which is an RNA-basedtechnology that enables the specific mapping and manipulation of gene expression in living cells. sxRNA isbased on the binding of one RNA molecule to a second RNA molecule in a manner designed to "switch" thestructural confirmation of the first RNA into an active "functional" form. The presence of a selected cellularmicroRNAs is then used to turn ON the translational activity of an sxRNA engineered mRNA by interacting withit in a manner that creates a new binding site for a protein that regulates translation. The objective of this STTRis to adapt the sxRNA technology, which is well established in traditional plated cell culture, to function as a toolfor screening of AD/ADRD drug candidates that limit senescence engagement in complex 3D human-cellcultures 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 ofsenescence in complex 3D tissue models. We will begin by developing an appropriate delivery vehicle forintroducing 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 atherapeutic SENsxRNA to selectively eliminate and/or modulate cells from the 3D tissues. This will pave the wayfor sxRNA Tech commercialization of products that enhance 3D tissue model expansion while increasingstandardization, providing new value to customers.
Public Health Relevance Statement: Narrative - Alzheimer's disease (AD) drug development has been an unfruitful and uphill battle leading to extremely limited therapeutic options and expensive clinical trials which ultimately end in failure. One of the causes of inefficient pharmaceutical identification and development of AD drugs is a lack of suitable model systems for high- throughput screening of senolytics and other AD therapeutics. sxRNA Technologies (sxRNA Tech) is developing an 3D human cell culture toolkit for Alzheimer's Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD) that has the potential to distinguish senescent cells in real-time to be used to enable the in vitro validation of senolytic drugs using human-cell-based, 3D-cultures, enabling a greater understanding of the aging processes, cell death, quiescence, and senescence as it relates to Alzheimer's Disease (AD) and Alzheimer's- Disease-Related Dementias (ADRD).
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