Chogen

ADVANCED COMPRESSORS FOR CO2-BASED POWER CYCLES AND ENERGY

ECHOGEN POWER SYSTEMS (DE), INC.: NEW DAYS AWARD. CONTROL NUMBER: 1906-1618 TITLE: ''LOW-COST, LONG DURATION ELECTRICAL ENERGY STORAGE USING A C02-BASED PUMPED THERMAL ENERGY STORAGE (PTES) SYSTEM'' ECHOGEN POWER SYSTEMS (DE), INC. WILL DEVELOP A LOW-COST, HIGH PERFORMANCE PUMPED THERMAL ENERGY STORAGE (PTES) TECHNOLOGY USING A CO2 WORKING FLUID FOR LONG-DURATION ELECTRICAL ENERGY STORAGE, AND EXTREMELY LOW-COST THERMAL STORAGE MATERIALS. ----------

DE-FE0031585 PROJECT TITLE: SUPERCRITICAL CARBON DIOXIDE PRIMARY POWER LARGE - SCALE PILOT PLANT

CO2 HIGH TEMPERATURE HEAT PUMP (HTHP)

EEG SIGNATURE ANALYSIS FOR DRUG REPURPOSING FOR RARE DISEASES - PROJECT SUMMARY THE HIGH RATE OF FAILURE IN CNS DRUG DISCOVERY, IN PARTICULAR OF THE FIRST-IN-CLASS THERAPEUTICS WITH NEW MODES OF ACTION, HIGHLIGHTS A CLEAR UNMET NEED TO IMPROVE THE SUCCESS RATE IN DRUG DISCOVERY FOR RARE DISEASES AND PSYCHIATRIC DISORDERS. ONE WELL-KNOWN ISSUE IS THE HIGH COST, HIGH RISK, AND LOW DEVELOPMENT TIME FOR DRUG DEVELOPMENT, TIME, AND COSTS THAT MOST OF THE 10,000 RARE DISORDER PATIENTS AND SUPPORT ORGANIZATIONS CANNOT AFFORD TO SUPPORT OR WAIT FOR. ANOTHER IMPORTANT ISSUE IS THE LACK OF CLEAR TARGETS FOR MANY FOR MOST RARE DISEASES, WHICH ARE COMPLEX AND MAY REQUIRE POLYPHARMACOLOGY. PHENOTYPIC SCREENING PLATFORMS ARE WELL-SUITED FOR DRUG REPURPOSING OF DRUG IN A TARGET-AGNOSTIC MANNER. SUITABLE PROVEN IN VIVO PHENOTYPIC SCREENS, HOWEVER, ARE SCARCE WITH THE EXCEPTION OF PSYCHOGENICS SMARTCUBE® PLATFORM, WHICH HAS BEEN DEVELOPED IN THE PAST FEW YEARS FOR DRUG REPURPOSING APPROACHES USING BEHAVIORAL DATA, COMBINING REFERENCE DRUGS’ SIGNATURES, AND COMPARING THEM AGAINST DISEASE ANIMAL MODELS’ SIGNATURES. OUR AIM FOR THIS FAST TRACK PROJECT IS TO CREATE A SIMILAR REPURPOSING PLATFORM BASED ON EEG DATA, USING OUR ECUBE® FAST EEG PLATFORM. TO DO THIS WE WILL ASSESS IN ECUBE® SEVERAL ANIMAL MODELS OF RARE DISEASE TO CREATE A SMALL DATABASE, INCREASE OUR REFERENCE DRUG EEG DATABASE, AND USE A NOVEL ALGORITHM, CALLED DRUG EEG SIGNATURE ANALYSIS (DESA) TO COMPARE THE TWO DATASETS AND GENERATE AT ONCE A MULTITUDE OF HYPOTHESES FOR POTENTIAL DRUG REPURPOSING. THESE HYPOTHESES TO BE EVALUATED EMPIRICALLY USING SUCH MODELS OF DISEASE. IF OUR PHASE I PROOF OF CONCEPT PROJECT IS SUCCESSFUL, WE WILL USE THE PHASE II PERIOD TO GET THE PLATFORM READY FOR COMMERCIALIZATION. IF SUCCESSFUL, THIS PLATFORM WILL BE AN INNOVATIVE AND UNIQUE DRUG REPURPOSING PLATFORM, OFFERED AS FEE-FOR-SERVICE OR USED IN DRUG DEVELOPMENT BY PGI AND ITS PARTNERS.

SCO2 POWER CYCLE WITH INTEGRATED THERMOCHEMICAL ENERGY STORAGE USING AN MGO-BASED SCO2 SORBENT IN DIRECT CONTACT WITH WORKING FLUID

DEVELOP AND DEMONSTRATE IWS SYSTEM AT LAB-SCALE, DEMONSTRATE ON PILOT-SCALE SYSTEM.

MACHINE LEARNING PHENOTYPIC DE NOVO DRUG DESIGN - PROJECT SUMMARY THE HIGH RATE OF FAILURE IN CNS DRUG DISCOVERY, IN PARTICULAR OF THE FIRST-IN-CLASS THERAPEUTICS WITH NEW MODES OF ACTION, HIGHLIGHTS A CLEAR UNMET NEED TO IMPROVE THE SUCCESS RATE IN DRUG DISCOVERY FOR PSYCHIATRIC DISORDERS. ONE WELL-KNOWN ISSUE IS THE POOR ABILITY OF CURRENT BIOASSAYS AND ANIMAL MODELS TO PREDICT THE EFFICACY AND SIDE- EFFECTS OF COMPOUNDS. ANOTHER IMPORTANT ISSUE IS THE LACK OF CLEAR TARGETS FOR CNS DISORDERS, WHICH ARE COMPLEX AND REQUIRE POLYPHARMACOLOGY. PHENOTYPIC SCREENING PLATFORMS ARE WELL-SUITED FOR DRUG DISCOVERY OF COMPOUNDS IN A TARGET-AGNOSTIC MANNER, ALLOWING FOR THE DISCOVERY AND DEVELOPMENT OF POLY PHARMACOLOGICAL AGENTS. SUITABLE PROVEN IN VIVO PHENOTYPIC SCREENS, HOWEVER, ARE RARE WITH THE EXCEPTION OF PSYCHOGENICS SMARTCUBE® PLATFORM, WHICH HAS BEEN USED TO SCREENED ~8000 COMPOUNDS AND REFERENCE DRUGS. COMPOUND AVAILABILITY FOR PHENOTYPIC SCREENING, HOWEVER, RESTRICT DISCOVERY TO KNOWN CHEMICAL SPACES. NOVEL MACHINE LEARNING METHODS ARE NOW AVAILABLE TO DESIGN NOVEL DRUGS THAT CAN BE USED TO POKE UNEXPLORED CHEMICAL SPACES. THE COMBINATION OF A MACHINE LEARNING MODEL CAPTURING STRUCTURE-TO-PHENOTYPE RELATIONSHIPS AND A MODEL THAT CAN GENERATE NOVEL DRUG-LIKE COMPOUNDS PROMISES TO DELIVER A TRULY NOVEL PLATFORM. OUR AIMS THEREFORE ARE 1) TO GENERATE A STRUCTURE- TO-PHENOTYPE MACHINE LEARNING MODEL (“PHENCHEML”) USING OUR COLLECTION OF MORE THAN 8000 COMPOUNDS AND DRUGS SCREENED IN PSYCHOGENICS’ SMARTCUBE® PHENOTYPIC IN VIVO PLATFORM, AND 2) TO COMBINE SUCH MODEL WITH COLLABORATION PHARMA DE NOVO DRUG DESIGN GENERATIVE MACHINE LEARNING MODEL MEGASYN®, AND GENERATE NOVEL CNS DRUG-LIKE COMPOUNDS FOR TESTING IN VIVO. THE SUCCESS OF THIS PHASE I SBIR PROJECT WILL RESULT IN PHENCHEML, A NOVEL PHENOTYPIC MACHINE LEARNING-BASED DRUG DISCOVERY PLATFORM THAT CAN GENERATE NOVEL CHEMOTYPES AND PREDICT THEIR THERAPEUTIC VALUE. IF OUR PHASE I PROJECT IS SUCCESSFUL, WE WILL EXTEND IT IN A PHASE II APPLICATION THROUGH THE DESIGN AND SYNTHESIS OF NOVEL MOLECULES FOR TEST IN SMARTCUBE® AND VALIDATION IN SECOND TIER ASSAYS FOCUSING ON PSYCHIATRIC DISORDERS (DEPRESSION, ANXIETY, PSYCHOSIS, AND BIPOLAR DISORDER). WE WILL ALSO EXPLORE THE USE OF THE PLATFORM FOR GENERATION OF NOVEL COMPOUNDS WITH POTENTIAL THERAPEUTIC EFFECTS IN MODEL SYSTEMS OF PSYCHIATRIC, NEURODEVELOPMENTAL, AND NEURODEGENERATIVE DISEASE (E.G., RETT, ASD, HD, PD, ETC). IF SUCCESSFUL, THIS PLATFORM WILL BE AN INNOVATIVE AND UNIQUE DRUG DESIGN METHOD, OFFERED BY AS FEE-FOR-SERVICE OR USED IN DRUG DEVELOPMENT BY PGI AND ITS PARTNERS.

DE-FE0031621, INTEGRATED OPTIMIZATION AND CONTROL OF A HYBRID GAS TURBINE/SUPERCRITICAL CARBON DIOXIDE(SCO2) POWER SYSTEM

DEVELOPMENT OF A DRUG CANDIDATE FOR THE TREATMENT OF AGITATION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY / ABSTRACT ALZHEIMER’S DISEASE (AD) IS A HIGHLY PREVALENT NEURODEGENERATIVE DISEASE CURRENTLY AFFECTING APPROXIMATELY 6.2 MILLION AMERICANS. AD IRREVERSIBLY DAMAGES THE CENTRAL NERVOUS SYSTEM, THEREBY INDUCING A VARIETY OF COGNITIVE, BEHAVIORAL, AND PSYCHIATRIC DISTURBANCES THAT INCLUDE AGITATION AND AGGRESSION. AD AGGRESSION OCCURS IN APPROXIMATELY A THIRD OF AD PATIENTS AND MEANINGFULLY REDUCES PATIENT AND CAREGIVER QUALITY OF LIFE. CURRENTLY AVAILABLE PHARMACOLOGICAL TREATMENTS FOR AD AGGRESSION CENTER ON THE USE OF ATYPICAL ANTIPSYCHOTIC DRUGS, WHICH HAVE MODEST EFFICACY ONLY AFTER CHRONIC ADMINISTRATION, AND ARE ASSOCIATED WITH SEDATION AS WELL AS ADVERSE EVENTS INCLUDING INCREASED RATES OF UPPER RESPIRATORY TRACT INFECTIONS, CARDIOVASCULAR EVENTS, FALLS, AND MORTALITY. GIVEN THE MODEST EFFICACY AND POOR SAFETY PROFILE OF THESE TREATMENTS, IDENTIFICATION OF NOVEL TREATMENTS FOR AD AGGRESSION WITH IMPROVED EFFICACY AND SAFETY IS AN IMPORTANT UNMET NEED. THE LONG-TERM GOAL OF THIS PROJECT IS TO BRING TO MARKET A NEW TREATMENT FOR AD AGGRESSION TO IMPROVE THE QUALITY OF LIFE FOR PEOPLE WITH AD AND THEIR CAREGIVERS. WE HAVE DISCOVERED A LEAD DRUG CANDIDATE, PGI-5128, THAT HAS A NOVEL MECHANISM OF ACTION TO PRODUCE SERENIC-LIKE EFFECTS IN RODENT MODELS OF AGGRESSION. PHASE I OF THIS PROJECT SEEKS TO EVALUATE THE EFFICACY OF PGI-5128 IN REDUCING AGGRESSIVE BEHAVIORS IN MALE AND FEMALE TRANSGENIC AD (APP/PS1) MICE. PHASE II SEEKS TO INITIATE INVESTIGATIONAL NEW DRUG (IND)-ENABLING NON-CLINICAL SAFETY AND TOXICOLOGY STUDIES IN RATS AND DOGS CONDUCTED ACCORDING TO GOOD LABORATORY PROCEDURES (GLP). SPECIFICALLY, STUDIES WILL INCLUDE 28-DAY REPEAT DOSE TOXICOLOGY STUDIES WITH 14-DAY RECOVERY PERIODS IN RAT AND DOG, GENOTOXICOLOGY STUDIES INCLUDING IN VITRO BACTERIAL REVERSE MUTATION AND IN VITRO AND IN VIVO MICRONUCLEUS TESTS, AND SAFETY PHARMACOLOGY STUDIES INCLUDING IN VITRO MANUAL PATCH CLAMP-BASED MEASURES AT THE HUMAN ETHER-À-GO-GO (HERG) CHANNEL, CNS AND BEHAVIORAL AND SAFETY PHARMACOLOGY STUDIES IN RATS, A RESPIRATORY SAFETY STUDY IN RATS, AND A CARDIOVASCULAR SAFETY STUDY IN DOGS. COMPLETING THESE STUDIES WILL POSITION PGI-5128 FOR AN IND APPLICATION TO ALLOW EVALUATION IN HUMAN SUBJECTS.

TAAR1 AGONISTS FOR THE TREATMENT OF STIMULANT USE DISORDER - PROJECT SUMMARY / ABSTRACT COCAINE USE DISORDER (CUD) IS A SERIOUS PUBLIC HEALTH CONCERN IN THE UNITED STATES. APPROXIMATELY 0.5% OF THE US POPULATION HAVE CUD, AND THESE PEOPLE ARE MORE PRONE TO DEATH, PARTICULARLY BY OVERDOSE, SUICIDE, AND CARDIOVASCULAR EVENTS. CUD TREATMENT FOCUSES ON PSYCHOLOGICAL THERAPIES, WHICH ARE EXPENSIVE AND ONLY MODERATELY EFFECTIVE. THERE ARE NO APPROVED MEDICATIONS FOR CUD, THUS IDENTIFYING NOVEL PHARMACOTHERAPIES FOR THIS DISORDER IS AN IMPORTANT UNMET NEED. THE LONG-TERM GOAL OF THIS PROJECT IS TO BRING TO MARKET A SAFE AND EFFECTIVE PHARMACEUTICAL DRUG TREATMENT THAT LEVERAGES NOVEL MECHANISMS OF ACTION TO REDUCE COCAINE USE AND IMPROVE ABSTINENCE. WE HAVE DISCOVERED TWO MOLECULES FEATURING DIFFERENT MECHANISMS OF ACTION THAT MAY PLAUSIBLY BE EFFECTIVE IN TREATING CUD. THE CURRENT PROJECT WILL EVALUATE THESE TWO COMPOUNDS FOR THEIR EFFECTS IN BEHAVIORAL MODELS EVALUATING COCAINE- AND NON-DRUG-RELATED REINFORCEMENT, AND STRESS-INDUCED REINSTATEMENT OF DRUG-SEEKING BEHAVIOR. SPECIFICALLY, WE WILL EVALUATE THE ABILITY OF THESE TWO MOLECULES TO REDUCE THE NUMBER OF COCAINE INFUSIONS IN COCAINE SELF-ADMINISTRATION STUDIES BASED ON A FIXED RATIO SCHEDULE OF REINFORCEMENT. WE WILL THEN EVALUATE THE MOST EFFECTIVE MOLECULE IN A STRESS-INDUCED REINSTATEMENT ASSAY, WHICH EVALUATES THE ABILITY OF THE COMPOUND TO PREVENT A RELAPSE INDUCED BY STRESS AFTER A DRUG-FREE PERIOD. IF OUR COMPOUND IS EFFECTIVE WITH A SINGLE DOSE, WE WILL EXAMINE WHETHER IT REMAINS EFFECTIVE AT SUPPRESSING STRESS-INDUCED REINSTATEMENT AFTER REPEATED ADMINISTRATION. FINALLY, WE WILL EVALUATE WHETHER THE EFFECTS OF THE COMPOUND ALSO MODIFY THE REINFORCING VALUE OF FOOD IN A FIXED RATIO SCHEDULE OF REINFORCEMENT. THE RESULTING DATA WILL HELP US UNDERSTAND TO WHAT EXTENT THE EFFECTS OF THE COMPOUND ARE SELECTIVE FOR DRUG AND NON-DRUG REINFORCERS.

CELL TYPE-SPECIFIC GENE THERAPY APPROACH FOR TOMT-LINKED CONGENITAL HEARING LOSS - PROJECT SUMMARY/ABSTRACT HEARING LOSS IS ONE OF THE MOST PREVALENT SENSORY DEFICITS, YET THERE ARE NO FDA-APPROVED BIOLOGICAL THERAPIES. THERE ARE OVER 100 DISTINCT FORMS OF NONSYNDROMIC GENETIC HEARING LOSS, EACH CAUSED BY MUTATIONS IN DIFFERENT GENES. ADVANCES IN ADENO-ASSOCIATED VIRAL (AAV)-BASED GENE THERAPIES FOR OTOFERLIN-LINKED GENETIC HEARING LOSS HAVE SHOWN GREAT PROMISE FOR TRANSLATING THERAPEUTICS DEVELOPED IN MOUSE MODELS TO HUMANS. HOWEVER, MANY CHALLENGES EXIST, AND MOST GENE THERAPIES LEAD TO INCOMPLETE HEARING RESTORATION AND MAY CAUSE SIDE EFFECTS. NAMELY, THE COCHLEAR EXPRESSION PATTERNS AND LEVELS, AND THE STRUCTURAL AND FUNCTIONAL IMPACTS OF DEAFNESS- LINKED MUTATIONS ARE GENE- AND CELL-TYPE-SPECIFIC. THUS, A ONE-SIZE-FITS-ALL APPROACH IS NOT OPTIMAL FOR HEARING LOSS GENE THERAPIES, AND THE DEVELOPMENT OF PRECISION, CELL-TYPE-SPECIFIC THERAPIES IS AN ESSENTIAL UNMET NEED. TO ESTABLISH A CELL-TYPE-SPECIFIC, PRECISION MEDICINE APPROACH FOR MAXIMAL THERAPEUTIC BENEFIT AND MINIMAL ADVERSE EFFECTS, WE FORMED ECHOGENESIS THERAPEUTICS. WE USED A COMPUTATIONAL APPROACH WITH IN VIVO SCREENING OF CANDIDATES TO GENERATE CANDIDATE CELL-TYPE-SPECIFIC GENOMIC PROMOTER FRAGMENTS FOR PRECISE THERAPEUTIC EXPRESSION. USING THIS PLATFORM APPROACH, WE DISCOVERED A NOVEL PROMOTER THAT IS HIGHLY SPECIFIC FOR COCHLEAR HAIR CELLS. HERE, WE PRESENT PROOF-OF-CONCEPT OF OUR PLATFORM FOR THE DEVELOPMENT OF OUR FIRST TARGET CELL-TYPE-SPECIFIC THERAPY FOR CONGENITAL GENETIC HEARING LOSS. MUTATIONS IN TOMT/LRTOMT/COMT2 (TOMT) CAUSE PROFOUND HEARING LOSS IN HUMANS—0.5% TO 8% OF ALL CASES OF GENETIC HEARING LOSS, DEPENDING ON THE POPULATION SAMPLED. MOUSE MODELS WITH TOMT MUTATIONS FAITHFULLY RECAPITULATE THE HUMAN HEARING LOSS PHENOTYPE. CONSISTENT WITH OUR HYPOTHESIS FOR THE NEED FOR CELL-TYPE-SPECIFIC GENE THERAPIES, WE FOUND THAT INNER- EAR DELIVERY OF TOMT DRIVEN BY GENE THERAPIES UTILIZING PROMOTERS CURRENTLY USED FOR HEARING LOSS GENE THERAPY LED TO SIGNIFICANT HEARING LOSS, AS EVIDENCED BY ELEVATED AUDITORY BRAINSTEM RESPONSE (ABR) THRESHOLDS IN NORMAL HEARING MICE. USING OUR NOVEL HAIR-CELL-TYPE-SPECIFIC PROMOTER, WE FOUND THAT OUR CELL-TYPE SPECIFIC APPROACH: 1) IS MUCH MORE SPECIFIC FOR HAIR CELLS THAN OTHER PROMOTERS; 2) SIGNIFICANTLY RESTORES ABR THRESHOLDS IN CONGENITALLY DEAF TOMT MUTANT MICE; AND 3) DOES NOT CAUSE HEARING DEFICITS IN NORMAL HEARING MICE, IN CONTRAST TO OTHER THERAPIES. THIS STTR PHASE I PROJECT WILL ADDRESS THE EFFICACY OF OUR AAV-BASED CELL-TYPE-SPECIFIC GENE THERAPY EXPRESSING HUMAN TOMT IN CONGENITALLY DEAF TOMT MUTANT MICE FOR HEARING RESTORATION. SPECIFICALLY, WE WILL 1) DETERMINE EFFECTIVE GENE THERAPY DOSAGES FOR HEARING RESTORATION; 2) DETERMINE THE TIMING WINDOW FOR THERAPEUTIC INTERVENTION; AND 3) DETERMINE THE DURATION OF THE THERAPEUTIC BENEFIT. OVERALL, OUR FINDINGS WILL HAVE SIGNIFICANT IMPLICATIONS FOR PATIENTS WITH HEREDITARY HEARING LOSS, INCLUDING THOSE WITH TOMT MUTATIONS, AND BROADER IMPACTS TOWARD IMPROVING THE UNDERSTANDING OF CELL-TYPE-SPECIFIC DELIVERY IN THE COCHLEA. IMPORTANTLY, OUR PROPOSED CELL- TYPE-SPECIFIC APPROACH WILL BE ALSO RELEVANT FOR OTHER FORMS OF HEARING LOSS WITH A GENE-RELATED ETIOLOGY OR GENETIC PREDISPOSITION, SUCH AS NOISE-INDUCED AND AGE-RELATED HEARING LOSS, AND FOR VESTIBULAR DISORDERS.

LOW-COST PARTICLE-TO-CO2 MOVING BED HEAT EXCHANGER

DEVELOPMENT OF A COMPACT DIRECT AIR TO CARBON DIOXIDE HEAT EXCHANGER

DEMONSTRATION OF A COMPACT HEAT EXCHANGER FOR SUPERCRITICAL CO2 HEAT RECOVERY SYSTEMS

A THERMALLY-DRIVEN TRANSCRITICAL CO2 HEAT PUMP FOR UPGRADING LWRGRADE HEAT TO HIGH TEMPERATURES