Project Grant R41AG081123

CREATING AN SXRNA ORGANOID PRODUCT FOR ADVANCING THE STUDY, PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE (AD) AND ALZHEIMER'S-DISEASE-RELATED DEMENTIAS (ADRD) - 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.