CHIMERNA THERAPEUTICS, INC.

842439913

2023

2

2816877549

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2025-01-22

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Department of Health and Human Services

SYNTHETIC BIOLOGY APPROACHES FOR BIO-ORTHOGONAL LABELING OF CIRCULAR RNAS - SUMMARY THE KEY CHALLENGES FOR RNA THERAPEUTICS ARE DELIVERY AND STABILITY INSIDE OF CELLS. CIRCULAR RNAS THAT LACK A 5’ AND 3’ END ARE RESISTANT TO INTRACELLULAR DEGRADATION, WHICH ALLOWS THEM TO PERSIST FOR MUCH LONGER THAN LINEAR RNAS. MEANWHILE LIPID NANOPARTICLE ENCAPSULATION OF RNA HAS IMPROVED STABILITY IN SERUM AND DELIVERY OF RNAS TO CELLS. HOWEVER, ALL RNA-BASED THERAPIES ARE CURRENTLY LIMITED BY INEFFICIENT ESCAPE FROM ENDOSOMES. EVEN WHEN ENCAPSULATED IN LNPS, LESS THAN 1% OF RNAS ARE ABLE TO EFFICIENTLY ESCAPE FROM ENDOSOMES. YET, EVIDENCE EXISTS THAT ENDOSOMAL ESCAPE OF SIRNAS CAN BE IMPROVED BY CONJUGATING RNA WITH HYDROPHOBIC LIPIDS. THESE GROUPS ARE THOUGHT TO DESTABILIZE THE ENDOSOME MEMBRANE, FACILITATING ESCAPE TO THE CYTOPLASM, WHERE THEY CAN EXERT THEIR THERAPEUTIC EFFECT. WHILE IT IS POSSIBLE TO ADD HYDROPHOBIC LIPIDS TO CHEMICALLY SYNTHESIZED SMALL RNAS, THIS IS MORE DIFFICULT FOR MRNAS AND CIRCULAR RNAS THAT ARE TYPICALLY PRODUCED BY IN VITRO TRANSCRIPTION. CHIMERNA SCIENTISTS HAVE DEVELOPED A HIGHLY EFFICIENT METHOD OF PRODUCING CIRCULAR RNAS IN BACTERIA. CHIMERNA HAS ALSO DEVELOPED A PROPRIETARY AFFINITY TAG TO PURIFY CIRCULAR RNAS FROM CRUDE LYSATES. THE RESULTING WORKFLOW IS RAPID, EFFICIENT, AND SCALABLE, WHILE GENERATING >90% PURE CIRCULAR RNA. CHIMERNA SCIENTISTS HAVE ALSO SHOWN THAT THE LIGATION JUNCTION OF THESE CIRCULAR RNA CAN BE MUTATED SO THAT THEY ARE SITE-SPECIFICALLY AMINO FUNCTIONALIZED BY AN ENDOGENOUS TRNA-GUANINE TRANSGLYCOSYLASE. THIS AMINO FUNCTIONAL GROUP CAN BE CONJUGATED LIPIDS THAT ARE WIDELY AVAILABLE OR ARE SIMPLE TO ACTIVATE FOR CONJUGATION USING A ROUTINE COUPLING METHOD. IN THIS WAY, CHIMERNA IS ABLE TO PRODUCE A VARIETY OF SITE-SPECIFICALLY LIPID-CONJUGATED CIRCULAR RNAS THAT MAY ACCELERATE ENDOSOMAL ESCAPE. IN THIS PROJECT, WE AIM TO 1) OPTIMIZE A BACTERIAL STRAIN AND EXPRESSION CONDITIONS FOR HIGH EFFICIENCY AMINO FUNCTIONALIZATION. THIS WILL INVOLVE KNOCKING OUT GENES DOWNSTREAM OF THE TRANSGLYCOSYLASE AND KNOCKING IN ADDITIONAL COPIES OF UPSTREAM GENES. 2) IMPROVE THE ENDOSOMAL ESCAPE OF RNAS BY SITE-SPECIFIC LIPID CONJUGATION. WE WILL TEST A VARIETY OF LIPID CONJUGATES TO A SMALLER CIRCULAR RNA THAT IS A MIRNA SPONGE, AND A LARGER CIRCULAR MRNA THAT IS TRANSLATED BY CAP-INDEPENDENT TRANSLATION. BOTH RNAS WILL BE ENCAPSULATED USING STANDARD METHODS AND WE WILL TEST EFFICIENCY OF ENDOSOMAL ESCAPE. TAKEN TOGETHER, WE WILL GENERATE A SCALABLE AND LOW-COST METHOD FOR SEMI-SYNTHESIS OF SITE-SPECIFICALLY LABELED CIRCULAR RNAS. WE WILL LEVERAGE THIS APPROACH TO SOLVE THE ENDOSOMAL ESCAPE CHALLENGES OF RNA THERAPEUTICS DELIVERY.

302605.00

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2023-12-20

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Department of Health and Human Services

DEVELOPMENT OF CIRCRNA MANUFACTURING PLATFORM IN YEAST - SUMMARY: CIRCULAR RNAS (CIRCRNAS) ARE A NOVEL CLASS OF RNAS THAT HOLD IMMENSE POTENTIAL AS THERAPEUTICS DUE TO THEIR UNIQUE CELLULAR FUNCTIONS. HOWEVER, THE CHALLENGES ASSOCIATED WITH THEIR SYNTHESIS AND PURIFICATION HAVE IMPEDED THEIR RESEARCH AND DEVELOPMENT. CHIMERNA PROPOSES TO DEVELOP A PLATFORM TECHNOLOGY USING YEAST TO MANUFACTURE HIGH-QUALITY CIRCRNAS FOR USE IN RESEARCH, THERAPEUTICS, AND DIAGNOSTICS. THE PROPOSED TECHNOLOGY BUILDS UPON CHIMERNA'S TORNADO TECHNOLOGY FOR EXPRESSING RNAS AS A CIRCLE IN CELLS. WHEN USED IN E. COLI, THE TORNADO TECHNOLOGY RESULTS IN THE PRODUCTION OF RNA AT HIGH LEVELS NOT PREVIOUSLY SEEN WITH CONVENTIONAL LINEAR RNAS. THE STABILITY OF CIRCULAR RNA ALLOWS IT TO ACCUMULATE TO HIGH LEVELS IN E. COLI, AND ALSO CONFERS HIGH STABILITY IN VITRO AND WHEN TRANSFECTED INTO MAMMALIAN CELLS, THUS MITIGATING THE PERSISTENT DEGRADATION PROBLEM OF CONVENTIONAL LINEAR RNAS. THE PROJECT ALSO UTILIZES A PROPRIETARY AFFINITY TAG THAT IS ENCODED INTO THE CIRCRNA MAKING DOWNSTREAM PURIFICATION EASIER. THIS TECHNOLOGY RESOLVES KEY PROBLEMS ASSOCIATED WITH CURRENT CIRCULAR RNA SYNTHESIS METHODS THAT USE IN VITRO TRANSCRIPTION FOR PRODUCTION. HOWEVER, PRODUCTION OF CIRCRNA IN E. COLI RESULTS IN HIGH LEVELS OF LPS, WHICH IS DIFFICULT TO REMOVE AND NOT ACCEPTABLE FOR THERAPEUTIC INDICATIONS. THE CURRENT PROPOSAL AIMS TO ENGINEER A YEAST STRAIN CAPABLE OF PRODUCING CIRCRNAS AT HIGH YIELDS. UNLIKE BACTERIA, YEAST DO NOT CONTAIN LPS, WHICH IS DIFFICULT TO REMOVE IN DOWNSTREAM PURIFICATION APPLICATIONS. MOREOVER, YEAST HAS BEEN EXTENSIVELY USED FOR MANUFACTURING MANY BIOACTIVE COMPOUNDS SUCH AS PROTEINS AND LIPIDS. THIS MAKES YEAST AN IDEAL ORGANISM IN WHICH TO DEVELOP A CIRCRNA MANUFACTURING PLATFORM. THE SPECIFIC AIMS OF THE PROJECT ARE: (1) - TO ENGINEER A YEAST STRAIN THAT CAN BE INDUCED TO EXPRESS CIRCULAR RNA AT HIGH YIELDS: THIS AIM INVOLVES ENGINEERING MULTIPLE YEAST STRAINS TO PRODUCE CIRCRNAS AND TESTING THEIR YIELD UNDER VARIOUS INDUCIBLE PROMOTERS. THE YEAST STRAIN WILL BE FURTHER OPTIMIZED BY INTRODUCING RNA PROCESSING ENZYMES REQUIRED FOR MAXIMUM CIRCULARIZATION EFFICIENCY; (2) TO BENCHMARK CIRCRNA MANUFACTURING TO EXISTING MANUFACTURING TECHNOLOGIES: THE SECOND AIM OF THE PROJECT INVOLVES COMPARING THE YIELD AND COST PER GRAM OF RNA PRODUCED IN YEAST VERSUS TRADITIONAL IVT. THE RESEARCHERS WILL ALSO EXAMINE PROTEIN EXPRESSION AND RNA HALF-LIFE FROM A CIRCULAR MRNA VERSUS A LINEAR MRNA FOR TOTAL PROTEIN OUTPUT IN MAMMALIAN CELLS. FINALLY, THEY WILL MEASURE INFLAMMATORY RESPONSES TO TRANSFECTED CIRCRNAS VERSUS LINEAR MRNAS. TAKEN TOGETHER, THE DEVELOPMENT OF A YEAST MANUFACTURING PLATFORM FOR SYNTHESIZING CIRCRNAS HOLDS IMMENSE PROMISE FOR THE PRODUCTION OF THIS HIGHLY IMPORTANT TYPE OF RNA. THE PROPOSED TECHNOLOGY WILL GREATLY REDUCE THE COST OF PRODUCING CIRCRNAS WHILE ALSO SIMPLIFYING THE PURIFICATION AND DOWNSTREAM PROCESSING. THIS NEW MANUFACTURING PLATFORM WILL ACCELERATE THE ENTRY OF CIRCRNAS FOR MEDICAL USE, THEREBY ADVANCING THE FIELD OF RNA THERAPEUTICS.

297608.00

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2022-09-07

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Department of Health and Human Services

A NOVEL TDP-43-TARGETING CIRCULAR RNA TO TREAT AMYOTROPHIC LATERAL SCLEROSIS (ALS) - SUMMARY AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A FATAL NEURODEGENERATIVE DISEASE CHARACTERIZED BY INCLUSION BODIES CONTAINING THE TDP-43 PROTEIN IN THE CYTOPLASM OF MOTOR NEURONS. THESE INCLUSION BODIES ARE CAUSED BY TDP- 43 AGGREGATION, WHICH IS CAUSED BY PATHWAYS OR MUTATIONS THAT CAUSE TDP-43 TO LOCALIZE TO THE CYTOPLASM. TDP-43 IS AN RNA-BINDING PROTEIN AND ITS ABILITY TO BIND MRNA IS A CRITICAL STEP IN THE PROCESS THAT ULTIMATELY LEADS TO TDP-43 AGGREGATES. WHEN TDP-43 BINDS CELLULAR RNAS, IT CAN “PHASE SEPARATE” AND BECOME ENRICHED IN STRESS GRANULES, WHERE TDP-43 SLOWLY FORMS INSOLUBLE AGGREGATES. A WIDELY ACCEPTED THERAPEUTIC GOAL IS TO PREVENT TDP-43 FROM UNDERGOING PHASE SEPARATION INTO STRESS GRANULES, SINCE THIS IS A PREREQUISITE FOR TDP-43 AGGREGATION. TO BLOCK TDP-43 PHASE SEPARATION, WE ARE USING RNA APTAMERS THAT BIND TDP-43’S RNA-BINDING DOMAIN AND THUS ACT AS A “DECOY” TO BLOCK TDP-43 FROM BINDING TO CELLULAR MRNA. HOWEVER, RNA APTAMERS ARE RAPIDLY DEGRADED IN THE CYTOSOL. CHIMERNA SCIENTISTS HAVE DEVELOPED AN INNOVATIVE EXPRESSION SYSTEM THAT ALLOWS RNA APTAMERS TO RAPIDLY BE CONVERTED INTO “CIRCULAR” RNAS IN CELLS, THUS MAKING THEM RESISTANT TO CELLULAR EXONUCLEASES. THIS DRAMATICALLY INCREASES RNA APTAMER STABILITY, LEADING TO EXPRESSION LEVELS THAT ARE AT LEAST 100 TIMES HIGHER THAN ANY PREVIOUS EXPRESSION SYSTEM. USING THIS SYSTEM, WE FOUND THAT CIRCULAR TDP-43-BINDING APTAMERS CAN BLOCK PHASE SEPARATION OF TDP-43 USING AN OPTOGENETIC TDP-43 PHASE-SEPARATION ASSAY. SINCE THE CIRCULAR RNAS ARE CYTOSOLIC, THEY SELECTIVELY BLOCK THE CYTOSOLIC FORM OF TDP-43 WITHOUT AFFECTING THE NORMAL FUNCTION OF TDP-43 IN THE NUCLEUS. THE CRITICAL QUESTION IS WHETHER TDP-43-BINDING APTAMERS WILL PREVENT TDP-43 AGGREGATION, TOXICITY, AND NEURODEGENERATION IN DISEASE- RELEVANT MODELS. TO TEST THIS, THE SPECIFIC AIMS OF THIS PROPOSAL ARE: (1) TO EVOLVE TDP-43 APTAMERS FOR HIGHER AFFINITY AND LOWEST IC50 FOR BLOCKING PHASE SEPARATION. WE WILL USE DIRECTED EVOLUTION TO EVOLVE HIGH-AFFINITY TDP-43 APTAMERS. WE WILL USE OUR OPTOGENETIC PLATFORM FOR INDUCING TDP-43 PHASE SEPARATION IN CELLS TO CALCULATE IC50 VALUES FOR THE TOP EVOLVED APTAMERS. THESE EXPERIMENTS WILL REVEAL THE APTAMERS THAT HAVE THE GREATEST POTENTIAL TO DISRUPT TDP-43 PHASE SEPARATION. (2) TO TEST THE ABILITY OF CIRCULAR TDP-43 APTAMERS TO BLOCK PHASE SEPARATION, AGGREGATION, AND TOXICITY OF TDP-43 IN HUMAN IPS NEURONS. HERE, WE WILL USE IPS-DERIVED ALS MOTOR NEURONS THAT EXHIBIT TDP-43 AGGREGATES, MARKERS OF AGGREGATE TOXICITY, AND INCREASED SUSCEPTIBILITY TO OXIDATIVE STRESS-MEDIATED CELL DEATH. WE WILL DETERMINE IF TDP-43 APTAMERS CAN BLOCK THESE KEY PARAMETERS OF TDP-43 AGGREGATE TOXICITY, THUS PROVIDING CRITICAL DATA ABOUT THE VALIDITY OF OUR APTAMER APPROACH USING DISEASE-RELEVANT MODEL. OVERALL, THESE EXPERIMENTS WILL TEST A NEW CONCEPT FOR BLOCKING TDP-43 AGGREGATION USING HIGHLY STABLE CIRCULAR TDP-43 APTAMERS, THAT WILL BE TESTED USING AN OPTOGENETIC PHASE SEPARATION ASSAY AND ALS IPS-DERIVED MOTOR NEURONS.

256158.00

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2022-06-16

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Department of Health and Human Services

CIRCULAR RNA APTAMERS TO REGULATE IRON HOMEOSTASIS IN IRON OVERLOAD DISORDERS - SUMMARY: IRON OVERLOAD DISORDERS ARE CAUSED BY HOMEOSTATIC IMBALANCE OF IRON IN THE LIVER. EXCESS IRON PRODUCES REACTIVE OXYGEN SPECIES THAT INDUCE INFLAMMATION, FIBROSIS, AND CAUSE FERROPTOSIS, AN IRON-DEPENDENT FORM OF CELL DEATH. REDUCING IRON LEVELS HAS A THERAPEUTIC BENEFIT. ALTHOUGH CHELATING IRON IS APPEALING FOR THESE DISORDERS, IRON CHELATORS EXHIBIT POOR PHARMACOKINETICS AND INDUCE A COMPENSATORY IRON UPTAKE RESPONSE IN CELLS. IN THIS PROPOSAL, WE ARE PROPOSING A COMPLETELY NOVEL APPROACH FOR REMOVING IRON FROM HEPATOCYTES. OUR APPROACH TARGETS IRP1/2, THE PROTEINS THE CONTROL IRON HOMEOSTASIS. IRP1/2 BINDS “IRE” SEQUENCES FOUND IN CERTAIN MRNAS ONLY WHEN IRON LEVELS ARE LOW. IRP1/2 BINDING TO MRNA LEADS TO TRANSLATION OF PROTEINS THAT CAUSE IRON INFLUX IN CELLS. SINCE IRP1/2 IS ABNORMALLY ACTIVATED IN IRON OVERLOAD DISORDERS, BLOCKING THE IRP1/2'S RNA-BINDING ACTIVITY COULD REDUCE INTRACELLULAR IRON AND REDUCE FERROPTOSIS. SINCE IRP1/2 CANNOT BE TARGETED WITH SMALL MOLECULES OR SIRNA DUE TO AN ESSENTIAL FUNCTION OF IRP1, WE ARE PROPOSING A NEW THERAPEUTIC CONCEPT: WE ARE USING IRE SEQUENCES AS “DECOYS” TO BLOCK IRP1/2 FROM BINDING MRNA, THUS SIMULATING A “HIGH IRON” STATE, AND CAUSING THE CELL TO REDUCE CELLULAR IRON LEVELS. THIS APPROACH WOULD NORMALLY BE IMPOSSIBLE SINCE SMALL RNAS, LIKE THE IRE, ARE HIGHLY UNSTABLE IN CELLS. HOWEVER, CHIMERNA SCIENTISTS HAVE DEVELOPED A NEW STRATEGY TO STABILIZE THE IRE BY SYNTHESIZED THIS RNA AS AN RNA CIRCLE. WE FIND THAT THESE CIRCULAR IRES INDUCE A ROBUST IRON REMOVAL PROGRAM AND CAUSE CELLS TO BECOME RESISTANT TO FERROPTOSIS. AT THIS POINT, THE MAJOR QUESTION IS CAN THESE CIRCULAR IRES BE EFFECTIVELY TARGETED TO HEPATOCYTES AND DO THEY REACH A THERAPEUTIC CONCENTRATION. IN ORDER TO TEST THIS IDEA, THE SPECIFIC AIMS OF THIS PROPOSAL ARE: (1) TO OPTIMIZE THE DELIVERY AND DOSE OF CIRCULAR IRE RNA FOR PERTURBING CELLULAR IRON HOMEOSTASIS. WE WILL SYNTHESIZE CIRCULAR IRES WITH A TRIANTENNARY N- ACETYLGALACTOSAMINE THAT ALLOWS THE CIRCRNAS TO BE PREFERENTIALLY TAKEN UP BY THE LIVER (2) TO TEST THE ABILITY OF CIRCULAR IRES TO REDUCE FERROPTOSIS IN CULTURE MODELS OF IRON OVERLOAD DISORDERS. HERE, WE WILL USE AN IRON OVERLOAD DISORDER MODEL OF PRIMARY HUMAN HEPATOCYTES TREATED WITH FERRIC AMMONIUM CITRATE (FAC). PRIMARY HEPATOCYTES WILL BE TRANSFECTED WITH TRI(GALNAC)-MODIFIED CIRCULAR IRES. THESE COMPARISONS WILL ALLOW US TO DETERMINE WHETHER CIRCULAR IRES ARE AS, OR POTENTIALLY MORE EFFECTIVE, THAN STANDARD CHELATOR-BASED APPROACHES. OVERALL, THIS APPLICATION WILL (1) CREATE A FUNDAMENTALLY NEW TYPE OF RNA THERAPEUTIC; (2) TARGET CELLULAR IRON HOMEOSTASIS FOR THE FIRST TIME; AND (3) PROVIDE A FUNDAMENTALLY NEW APPROACH TO TREAT IRON OVERLOAD DISORDERS.

255236.00

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2024-03-28

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Department of Health and Human Services

CIRCULAR MIMICS OF IRON-RESPONSE ELEMENTS TO INHIBIT FERROPTOSIS - SUMMARY: IRON OVERLOAD IS FOUND IN NEARLY ALL PATIENTS WITH PARKINSON'S DISEASE AND CAN LEAD TO FERROPTOSIS, AN IRON-DEPENDENT FORM OF CELL DEATH. THE IMPORTANCE OF IRON IN PARKINSON'S DISEASE PATHOLOGY IS SUPPORTED BY THE BENEFICIAL EFFECTS OF IRON CHELATORS IN CULTURE AND ANIMAL MODELS OF PARKINSON'S DISEASE. HOWEVER, IRON CHELATORS HAVE POOR PHARMACOKINETICS, POOR BLOOD-BRAIN BARRIER PERMEABILITY, AND THEY ACTIVATE A COMPENSATORY CELLULAR RESPONSE THAT INVOLVES ACTIVATING IRON UPTAKE INTO CELLS. THUS, THE CELL'S COMPENSATORY RESPONSE TO CHELATORS COULD EVENTUALLY COUNTERACT ANY BENEFICIAL IRON-REMOVAL EFFECT OF THE CHELATOR. THEREFORE, IT IS IMPORTANT TO DEVELOP ALTERNATIVE IRON REMOVAL THERAPIES THAT MAY BE MORE EFFECTIVE THAN CONVENTIONAL CHELATORS. IN THIS PROPOSAL, WE ARE PROPOSING A COMPLETELY NOVEL APPROACH FOR REMOVING IRON FROM NEURONS. RATHER THAN USING A CHELATOR, WE ARE ACTIVATING THE CELL'S ENDOGENOUS IRON REMOVAL AND DETOXIFICATION PROGRAMS. IRON HOMEOSTASIS IN THE CELL RELIES ON TWO IRON-SENSING PROTEINS, IRP1 AND IRP2 (IRON-RESPONSE PROTEIN 1 AND 2). IRP1 AND 2 ARE RNA-BINDING PROTEINS THAT BIND TO MRNAS THAT CONTAIN AN IRE (IRON-RESPONSE ELEMENT) HAIRPIN SEQUENCE. INHIBITING IRP1 AND 2 WOULD CAUSE THE CELL TO ACTIVATE PATHWAYS THAT REDUCE INTRACELLULAR IRON LEVELS. WE ARE CREATING A NEW TYPE OF RNA THERAPY IN WHICH WE USE THE IRE RNA HAIRPIN AS A “DECOY” TO BLOCK IRP1 AND 2 FROM BINDING ITS TARGET MRNAS. ALTHOUGH SMALL RNAS ARE UNSTABLE IN CELLS, CHIMERNA HAS DEVELOPED A NOVEL TECHNOLOGY THAT ALLOWS SMALL RNAS TO BE RAPIDLY CIRCULARIZED, EITHER IN VITRO, OR WHEN EXPRESSED IN CELLS. OUR STUDIES IN HEK293 CELLS SHOW THAT CIRCULAR IRES INDUCE A ROBUST IRON REMOVAL PROGRAM AND CONFER RESISTANCE TO FERROPTOSIS. AT THIS POINT, THE MAJOR QUESTION IS WHETHER CIRCULAR IRES CAN BLOCK FERROPTOSIS IN MODELS OF PARKINSON'S DISEASE. IN ORDER TO TEST THIS IDEA, THE SPECIFIC AIMS OF THIS PROPOSAL ARE: (1) TO OPTIMIZE TRANSFECTION OF CIRCULAR IRE RNA AND CIRCULAR IRE- EXPRESSING PLASMIDS FOR IRON DEPLETION IN MESENCEPHALIC NEURONS. IN THIS AIM, WE WILL OPTIMIZE TWO DISTINCT DELIVERY MODES FOR CIRCULAR IRE RNAS: (A) DIRECT TRANSFECTION OF CIRCULAR IRE RNAS; AND (B) PLASMID- BASED EXPRESSION OF CIRCULAR IRES. WE WILL TEST THE EFFICIENCY OF TOTAL IRON REDUCTION, TRANSFERRIN RECEPTOR, FERRITIN AND FERROPORTIN LEVELS IN CULTURED NEURONS. OVERALL, THESE EXPERIMENTS WILL OPTIMIZE TWO DIFFERENT APPROACHES FOR ACHIEVING CIRCULAR IRE RNA IN NEURONS. (2) TO COMPARE DEFEROXAMINE AND CIRCULAR IRE AS INHIBITORS OF NEURODEGENERATION IN A CULTURED PARKINSON'S DISEASE MODEL NEURONS. HERE, WE WILL USE TWO PARKINSON'S DISEASE MODELS: MPTP TOXICITY AND ALPHA-SYNUCLEIN TOXICITY. WE WILL COMPARE CIRCULAR IRES TO DESFEROXAMINE, AND IRON CHELATOR, TO DETERMINE WHETHER CIRCULAR IRES ARE AS, OR POTENTIALLY MORE EFFECTIVE, THAN STANDARD CHELATOR-BASED APPROACHES. IF THESE APPROACHES ARE SUCCESSFUL, IT WOULD SUGGEST THAT IRP1/2 IS A THERAPEUTIC TARGET, AND THAT CIRCULAR RNAS REPRESENTED NEW MODALITY DISTINCT FROM SMALL MOLECULE CHELATORS FOR PARKINSON'S DISEASE.

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