Nopi Inc

PRECLINICAL DEVELOPMENT OF A NOVEL THERAPEUTIC FOR PARKINSON'S DISEASE - PROJECT SUMMARY PARKINSON’S DISEASE (PD) IS THE SECOND MOST COMMON NEURODEGENERATIVE DISORDER, AFFLICTING ~1 MILLION AMERICANS. LEVODOPA IS THE GOLD-STANDARD SYMPTOMATIC TREATMENT FOR PD BY ELEVATING DOPAMINE LEVELS IN THE BRAIN. THOUGH THE MOST EFFECTIVE TREATMENT, PROLONGED LEVODOPA USE LEADS TO 1) THE DEBILITATING SIDE EFFECT, LEVODOPA-INDUCED DYSKINESIA (LID), AND 2) DIMINISHED LEVODOPA EFFICACY WHICH LEADS TO FLUCTUATIONS OF PD SYMPTOMS, KNOWN AS “WEARING-OFF”. THESE CONCERNS ARE TWO OF THE GREATEST UNMET NEEDS IN PD AND AFFECT HOW DOCTORS PRESCRIBE DOSAGES AND TREATMENT OPTIONS, IMPACTING THE EFFICACY OF THE NECESSARY MEDICATIONS FOR PD. AFTER 5 YEARS OF LEVODOPA USAGE, 40% OF PD PATIENTS WILL DEVELOP LID AND/OR FLUCTUATIONS. NOT ONLY HAVING A CLINICAL IMPACT, BUT PD PATIENTS WITH SUCH COMPLICATIONS REQUIRE NEARLY $60,000 OF ADDITIONAL THERAPEUTICS EVERY YEAR. USING SINOPIA BIOSCIENCES’ COMPUTATIONAL PLATFORM, WE STUDIED GENE EXPRESSION CHANGES DUE TO LEVODOPA ADMINISTERED TO 6-OHDA LESIONED PD-LIKE MICE. APPLYING OUR COMPUTATIONAL WORKFLOW, WE IDENTIFIED A SMALL MOLECULE (SB-0107) THAT WAS SELECTED BASED ON: 1) HAVING ONE OF THE TOP SCORES FROM OUR PLATFORM, 2) ITS NOVEL MECHANISM OF ACTION, 3) PREVIOUS CLINICAL EXPOSURE TO ELDERLY PATIENTS, 4) ITS PREDICTED CNS PENETRATION PROPERTIES, AND 5) ITS POTENTIAL FOR PATENT PROTECTION. SUBSEQUENTLY, WE DEMONSTRATED THE COMPOUND’S UNIQUE AND POTENTIALLY TRANSFORMATIVE PHARMACOLOGY FOR TREATING BOTH THE SYMPTOMS OF PD AND COMPLICATIONS OF LEVODOPA (I.E. LID). IN BOTH RODENT AND PRIMATE MODELS, SB-0107 SHOWS LARGE EFFECT SIZES. FURTHER, WE OBSERVED IN A COGNITIVE DEFICIT PRIMATE MODEL OF PD THAT SB-0107 IMPROVES PERFORMANCES IN THE TESTED COGNITIVE TASKS. THUS, SB-0107 REPRESENTS A PROMISING CANDIDATE FOR ADVANCEMENT TO THE CLINIC FOR PD. IN THIS FAST-TRACK PROPOSAL, WE WILL ADVANCE THE COMPOUND BY COMPLETING PRECLINICAL DEVELOPMENT STUDIES FOR ANTICIPATION OF IND SUBMISSION.

EARLY AND ACCURATE DIAGNOSIS OF PULMONARY AND EXTRAPULMONARY TUBERCULOSIS IN ALL PATIENT GROUPS USING A CIRCULATING PATHOGEN-DERIVED ANTIGEN - PROJECT SUMMARY NANOPIN IS ADVANCING A DIAGNOSTIC FOR ACTIVE TUBERCULOSIS (TB) THAT ADDRESSES CRITICAL UNMET CLINICAL NEEDS AND ITS INNOVATION AND POTENTIAL PATIENT IMPACT HAS RESULTED IN DESIGNATION AS A BREAKTHROUGH DEVICE BY THE FDA. THIS DEVICE WILL HIGHLY VALUABLE IN THE GLOBAL EFFORT TO COMBAT TB, WHICH IS NOW THE LEADING CAUSE OF DEATH FROM INFECTIOUS DISEASE, WITH AN ESTIMATED 10.0 MILLION NEW TB CASES AND 1.5 MILLION TB-RELATED DEATHS ANNUALLY. KEY UNMET NEEDS FOR TB DIAGNOSIS INCLUDE A RAPID TEST THAT IS BOTH CULTURE-FREE AND NON-SPUTUM-BASED, IS ACTIONABLE AND INFORMATIVE ESPECIALLY IN COUNTRIES WITH HIGH LATENT TB RATES, CAN ACCURATELY DETECT BOTH PULMONARY AND EXTRAPULMONARY TB, AND CAN DETECT ACROSS THE ENTIRE PATIENT SPECTRUM INCLUDING YOUNG CHILDREN AND HIV- COINFECTED PATIENTS. NANOPIN’S HIGHLY SENSITIVE DIAGNOSTIC PLATFORM RAPIDLY DETECTS SPECIES-SPECIFIC TB ANTIGENS DIRECTLY FROM BLOOD SAMPLES. OUR TECHNOLOGY IS DIFFERENTIATED FROM ALL CURRENT METHODS IN THAT WE CAN DETECT TB NO MATTER WHERE IT IS IN THE BODY AND WHOSE BODY IT IS IN. WE CAN DETECT TB BASED IN THE LUNGS, KIDNEYS, BRAIN AND THROUGHOUT THE BODY, EVEN WHEN THE CURRENT “GOLD STANDARD” CANNOT. WE CAN DETECT IN DIFFICULT COHORTS INCLUDING YOUNG CHILDREN AND EVEN INFANTS AND HIV CO-INFECTED, ALL OF WHICH ARE POORLY SERVED IN THE MARKET AND WHERE CONVENTIONAL SPUTUM METHODS ARE NOT FEASIBLE. ULTIMATELY, THIS TECHNOLOGY WILL ENABLE HEALTH CARE PROVIDERS TO FINALLY MITIGATE THE ENDURING TB EPIDEMIC. THE OUTCOMES OF SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL INTRODUCE OUR TB DIAGNOSTIC DEVICE INTO THE MARKET AND MAKE IT AVAILABLE FOR ROUTINE USE IN CLINICS AND HOSPITALS BY EVALUATING ITS PERFORMANCE IN A WELL- STRUCTURED CLINICAL STUDY IN MULTIPLE HIGH PROFILE MEDICAL CENTERS. WE PROPOSE FOUR SPECIFIC AIMS: 1). TO PERFORM ANALYTICAL VALIDATION OF THE NANOTB ASSAY KIT AND MULTIPLE LC-MS PLATFORMS. PRIOR TO INITIATING CLINICAL STUDIES, WE WILL DETERMINE KEY QUANTITATIVE VALUES FOR THE TB ASSAY KITS INCLUDING LOD, LOQ, AND CUT-VALUES PER CLSI C62- A. WE WILL ESTABLISH MULTIPLE LC-MS PLATFORMS FOR CLINICAL STUDIES AND REGULATORY APPROVAL WHICH WILL FURTHER OUR COMMERCIALIZATION REACH; 2). TO PERFORM CLINICAL STUDIES FOR DETECTION OF ACTIVE TB WITH NANOTB DIAGNOSTIC ASSAY KITS. THE CLINICAL STUDIES PROPOSED IN THIS AIM WILL BE THE BASIS FOR 510K APPLICATION TO THE FDA FOR REGULATORY APPROVAL AND MARKETING OF THE NANODETECT-TB DEVICE. THE STUDIES WILL ENROLL PATIENTS SUSPECTED OF TB DISEASE AND ANALYZE WITH OUR TB ASSAY AND THE PRIMARY AFB-CULTURE REFERENCE METHOD; 3). TO COMMUNICATE WITH THE FDA FOR GUIDANCE FOR CLINICAL STUDIES AND 510K SUBMISSION. INTERACTIONS WITH THE FDA WILL GUIDE THE EFFICIENT AND SUCCESSFUL IMPLEMENTATION OF THE PROPOSED WORK. THE OUTCOME OF THIS AIM IS THE FDA CLEARANCE OF THE NANODETECTTB DEVICE VIA THE DE NOVO PATHWAY; AND 4). TO EXTEND CLINICAL STUDIES FOR PEDIATRIC CENTRIC AND RESOURCE LIMITED FOCUS. WE WILL FURTHER EVALUATE THE CRITICAL PEDIATRIC COHORT AND ADDRESS CHALLENGES FOR SAMPLE COLLECTION AND HANDLING SHIPPING IN RESOURCE LIMITED REGIONS IN ORDER TO ENSURE OUR APPLICATION CAN BE EXTENDED TO ALL PATIENTS.

PRECLINICAL ASSESSMENT OF A NOVEL COMPOUND FOR TREATING RADIATION-INDUCED ORAL MUCOSITIS - PROJECT SUMMARY INFLAMMATION AND ULCERATION OF MUCOSAL TISSUE, CALLED MUCOSITIS, IS A SEVERE SIDE EFFECT OF MANY COMMON TREATMENTS IN ONCOLOGY, INCLUDING CHEMO- AND RADIOTHERAPY. MUCOSITIS DEVELOPMENT IS COSTLY TO THE HEALTH CARE SYSTEM AND CAN LEAD TO POORER OUTCOMES FOR PATIENTS. MUCOSITIS OF THE MOUTH AND ESOPHAGUS, CALLED ORAL MUCOSITIS, IS PARTICULARLY COMMON IN HEAD AND NECK CANCER PATIENTS RECEIVING RADIATION THERAPY, WHERE ROUGHLY 80% OF PATIENTS DEVELOP THIS SIDE EFFECT. TREATING ORAL MUCOSITIS REMAINS A LARGE CLINICAL UNMET NEED WITH NO FDA APPROVED TREATMENTS. USING SINOPIA BIOSCIENCES’ COMPUTATIONAL PLATFORM, WE IDENTIFIED A TARGET CLASS AND AN ASSOCIATED SMALL MOLECULE FOR PREVENTING AND/OR TREATING MUCOSITIS. THE TARGET CLASS HAS AN ESTABLISHED SAFETY PROFILE IN PATIENTS WITH SOLID TUMORS. IN TWO STUDIES WITH THE ACUTE RADIATION-INDUCED HAMSTER MODEL OF ORAL MUCOSITIS, WE OBSERVED COMPELLING RESULTS THAT ORAL ADMINISTRATION OF THE COMPOUND SIGNIFICANTLY DECREASED THE DURATION OF ULCERATIVE MUCOSITIS AND IN SOME ANIMALS COMPLETELY PREVENTED THE DEVELOPMENT OF ULCERS. THE OBSERVED EFFECT SIZE WAS AS LARGE OR LARGER THAN OTHER COMPOUNDS CURRENTLY IN THE CLINIC TESTED IN THE SAME MODEL. THE TEST COMPOUND IS A PAN-INHIBITOR OF SEVERAL TARGETS IN THE TARGET CLASS, EACH WITH MULTIPLE BINDING DOMAINS. IN PHASE I, WE IDENTIFIED THE SPECIFIC DOMAIN WITHIN THIS TARGET CLASS THAT MOST SAFELY CONTRIBUTES TO MUCOSITIS AMELIORATION. SELECTIVE INHIBITION OF THIS DOMAIN RETAINS THE EFFICACY OF THE PAN-INHIBITOR, BUT AVOIDS THE GENERAL TOXICITY ISSUES SEEN WITH PAN-INHIBITION. IN THIS PHASE II PROPOSAL, WE WILL DEVELOP A NOVEL ORALLY BIOAVAILABLE COMPOUND THAT SELECTIVELY INHIBITS THIS SPECIFIC TARGET DOMAIN. WE WILL THEN CHARACTERIZE THIS NEW COMPOUND IN THE FRACTIONATED RADIATION MODEL OF ORAL MUCOSITIS MUCOSITIS TO ADVANCE THE PROGRAM TOWARDS THE CLINIC.

DEVELOPMENT OF A METABOLOMICS AND MACHINE LEARNING BASED HIGH-THROUGHPUT SCREENING PLATFORM FOR DATA-DRIVEN DRUG DISCOVERY - PROJECT SUMMARY HIGH-THROUGHPUT OMICS TECHNOLOGIES ALLOW FOR MEASURING VARIOUS BIOMOLECULES COMPREHENSIVELY AND OVER THE PAST DECADE HAVE BECOME EXPONENTIALLY LESS EXPENSIVE. COUPLING THESE EMERGING TECHNOLOGIES WITH AUTOMATION APPROACHES AND THE PHENOTYPIC-BASED DRUG DISCOVERY PARADIGM ALLOWS FOR DATA-DRIVEN DRUG DISCOVERY (D4). D4 FOCUSES ON A COMPLETE CELLULAR READOUT, QUANTITATIVELY MEASURING 100S TO 100,000S OF BIOMOLECULES OR CELLULAR FEATURES, RATHER THAN FOCUSING ON A SINGLE PROTEIN, PATHWAY, OR PHYSIOLOGICAL TRAIT. THE COMPLEXITY OF THIS DATA REQUIRES COMPUTATIONAL TOOLS FOR PROPER ANALYSIS AND INTERPRETATION. IN PHASE I OF THIS PROPOSAL, WE COMBINED THE DUAL STRENGTHS OF EXPERTS IN LC-MS/MS BASED METABOLOMICS (OMIX TECHNOLOGIES) WITH LEADERS IN METABOLOMICS DATA ANALYSIS (SINOPIA BIOSCIENCES) TO DEVELOP A METABOLOMICS BASED HIGH-THROUGHPUT SCREENING PLATFORM. WE SCREENED ~250 FDA APPROVED SMALL MOLECULES FROM A BROAD RANGE OF DRUG CLASSES ON TWO CELL LINES. THIS DATASET WAS COMPARED TO A MATCHING DATASET FROM THE PIONEERING PROJECT FOR D4, THE CONNECTIVITY MAP, WHICH IS A TRANSCRIPTOMICS SCREENING AND QUERY PLATFORM FOR DRUG CHARACTERIZATION, DISCOVERY, AND REPOSITIONING. IN PHASE I, WE OBSERVED THAT FROM BOTH A TECHNICAL AND BIOLOGICAL UTILITY STANDPOINT, THE METABOLOMICS DATA PROVIDED AN ORTHOGONAL DATASET WITH SIGNAL FIDELITY, SENSITIVITY, AND RELEVANCE TO COMPOUND PROPERTIES COMPARABLE TO OR EXCEEDING THE CONNECTIVITY MAP. FURTHER, WE SAW HIGH CONCORDANCE OF PLASMA METABOLITE CHANGES IN TYPE 2 DIABETES AND RHEUMATOID ARTHRITIS PATIENTS WITH IN VITRO METABOLITE CHANGES OF RELATED DRUGS USED FOR THOSE INDICATIONS. THUS, THESE RESULTS SUGGEST THAT A METABOLOMICS BASED HIGH-THROUGHPUT SCREENING PLATFORM IS NOT ONLY VIABLE AS A COMPLEMENTARY DATASET TO THE CONNECTIVITY MAP, BUT THAT METABOLOMICS DATA CAN EVEN PLAY A PRIMARY ROLE IN DRUG DISCOVERY. IN THIS PHASE II PROPOSAL, WE WILL FOCUS ON PROFILING CHEMICAL AND GENETIC PERTURBATIONS IN VITRO TO FURTHER DEMONSTRATE THE POWER OF THE PLATFORM AND IDENTIFY COMMERCIAL OPPORTUNITIES FOR TREATING GENETICALLY DEFINED RARE DISEASES. WE WILL EXPAND DATA GENERATION TO ~3300 BIOACTIVE COMPOUNDS ACROSS THREE CELL LINES. FURTHER, WE WILL PROFILE 50 GENETIC KNOCKOUTS ON THOSE THREE CELL LINES TO MODEL IN VITRO THE ASSOCIATED RARE DISEASES. USING SINOPIA’S PLATFORM, WE WILL SELECT COMPOUNDS FOR FOLLOW-UP EVALUATION TO IDENTIFY CANDIDATES THAT CORRECT FOR METABOLIC DYSREGULATIONS SEEN IN THOSE RARE DISEASES. SUCCESSFUL IN VITRO PROGRAMS WILL AID IN SEEDING OF AN EARLY STAGE DISCOVERY PIPELINE THAT WILL BE ADVANCED THROUGH FUNDING BY PRIVATE INVESTMENT, PATIENT ADVOCACY GROUPS, AND ADDITIONAL FEDERAL GRANTS.

SBIR PHASE II: FULL-SCALE DEMONSTRATION OF AUTONOMOUS ROBOTIC GREENHOUSE FOR SUSTAINABLE LOCAL FOOD PRODUCTION -THE BROADER/COMMERCIAL IMPACT OF THIS SMALL BUSINESS INNOVATION RESEARCH (SBIR) PHASE II PROJECT PROMOTES SMALL AND MID-SIZED FARMING IN THE UNITED STATES THROUGH ENVIRONMENTALLY FRIENDLY MEANS. THROUGH COST-EFFECTIVE LABOR AUTOMATION, A FULLY AUTOMATED, TURN-KEY GREENHOUSE PRODUCTION SYSTEM CAN BE MADE MORE ACCESSIBLE. THIS PROJECT WILL PROVIDE FARMERS WITH A TOOL THAT CAN GUARANTEE A BASELINE ANNUAL PRODUCTION OF LEAFY GREENS AND HERBS, INDEPENDENT OF WEATHER VARIABLES AND LABOR ACCESSIBILITY. BY REMOVING WEATHER LIMITATIONS AND LABOR REQUIREMENTS, SMALL AND MID-SIZED FARMS CAN BE MADE MORE PROFITABLE AND SCALABLE. THIS PROJECT WILL HAVE A POSITIVE IMPACT ON THE ADVANCEMENT OF LOCAL AND REGIONAL FOOD SYSTEMS. BY ADVANCING A MARKET THAT HAS BEEN HISTORICALLY IGNORED FROM A TECHNOLOGICAL STANDPOINT, AN ATTRACTIVE ALTERNATIVE TO LARGE-SCALE INDUSTRIAL AGRICULTURE AND FOREIGN FRESH FOOD IMPORTS WILL BE CREATED. MAKING SMALL AND MID-SIZED FARMS MORE ECONOMICALLY VIABLE WILL CREATE A MORE ROBUST AND SUSTAINABLE FOOD SYSTEM. THIS SBIR PHASE II EFFORT WILL DESIGN, BUILD, AND DEMONSTRATE A FULL-SCALE, AUTOMATED GREENHOUSE FARM PROTOTYPE. THIS PROTOTYPE WILL REMAIN COMPLETELY AUTONOMOUS FOR WEEKS AT A TIME REQUIRING NO HUMANS TO ENTER THE FARM WHILE ALL PROCESSES FROM SEED TO STORAGE OF HARVESTED CROPS ARE PERFORMED ROBOTICALLY. NO GREENHOUSE TECHNOLOGY, AT ANY PRICE POINT, HAS BEEN ABLE TO DEMONSTRATE AN ABILITY TO ACHIEVE THIS DEGREE OF AUTOMATION. THIS TECHNOLOGY WILL ADVANCE THE IMPLEMENTATION OF ROBOTICS IN FOOD PRODUCTION BY ADDRESSING THE CAPITAL COSTS, LABOR, AND ENERGY BARRIERS THAT CONTROLLED ENVIRONMENT AGRICULTURE SYSTEMS CURRENTLY FACE. KEY CHALLENGES INCLUDE THE PRODUCTION OF APPROXIMATELY 340 PLANTS PER DAY WITHOUT ANY HUMAN INTERVENTION, A LOW-COST DESIGN FOR SETUP AND ONGOING OPERATIONS, AND THE ABILITY TO ADJUST PRODUCT OUTPUTS IN REAL-TIME TO MEET MARKET DEMANDS. HUMAN INTERACTION WITH THE GROWING PROCESS WILL BE LIMITED THROUGH A HIGH DEGREE OF SYSTEM AUTOMATION, INCLUDING COMPUTER VISION FOR PLANT INSPECTIONS AND SELF-CLEANING PROCESSES. NOVEL PLANT GROWTH AND HANDLING PROCESSES WILL ALLOW FOR VIRTUALLY ANY TYPE OF LEAFY GREEN OR HERB TO BE GROWN. A VARIETY OF SENSORS WILL BE USED TO MONITOR CONDITIONS AND ADJUST THE SYSTEM, ALLOWING FRESH PRODUCE IN AREAS WITHOUT SUITABLE AGRICULTURAL OPPORTUNITIES. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

DEVELOPING A SYSTEMS BIOLOGY PLATFORM FOR PREDICTING, PREVENTING, AND TREATING DRUG SIDE EFFECTS

IMPROVING SAFETY AND EFFICACY OF PLATELET TRANSFUSION THROUGH SYSTEMS BIOLOGY

IMPROVING RED BLOOD CELL TRANSFUSION THROUGH SYSTEMS BIOLOGY

SBIR PHASE II: AI-DRIVEN 3D IMAGING AND VISUALIZATION FOR ENDOSCOPY

DEVELOPMENT OF A METABOLOMICS AND MACHINE LEARNING BASED HIGH-THROUGHPUT SCREENING PLATFORM FOR DATA-DRIVEN DRUG DISCOVERY

DEVELOPMENT OF NEURAL NETWORK MODELS TO ENABLE EFFICIENT METABOLOMIC CHARACTERIZATION OF COMPOUND LIBRARIES FOR DATA-DRIVEN DRUG DISCOVERY - PROJECT SUMMARY DATA-DRIVEN DRUG DISCOVERY (D4) COMBINES PHENOTYPIC-BASED DRUG DISCOVERY WITH HIGH-THROUGHPUT OMICS TECHNOLOGIES AND MACHINE LEARNING. LIKE PHENOTYPIC-BASED DRUG DISCOVERY, D4 IS UNBIASED, BUT IT OFFERS ADDITIONAL BIOMOLECULAR INSIGHTS BY LEVERAGING OMICS TECHNOLOGIES TO MEASURE 100S TO 100,000S OF BIOMOLECULES, ENABLING DEEP DISEASE AND COMPOUND CHARACTERIZATION. THE PREDOMINANT DATA TYPE FOR D4 HAS HISTORICALLY BEEN TRANSCRIPTOMICS AND, MORE RECENTLY, IMAGE-BASED ASSAYS HAVE BEEN UTILIZED. OTHER BIOMOLECULAR FEATURES (I.E., PROTEINS AND METABOLITES) ARE CONSIDERED CLOSER TO THE PHENOTYPE, BUT TECHNICAL CHALLENGES IN DATA GENERATION AND ANALYSIS, AS WELL AS THE LACK OF STANDARDIZED PIPELINES HAVE PRECLUDED THE SYSTEMATIC USE OF THESE DATA TYPES. SINOPIA BIOSCIENCE AND OMIX TECHNOLOGIES HAVE COMBINED THEIR STRENGTHS IN SYSTEMS BIOLOGY DATA ANALYSIS, AI/ML, AND LC-MS/MS BASED METABOLOMICS TO DEVELOP A UNIQUE METABOLOMICS-BASED DRUG DISCOVERY PLATFORM, AND USED THIS FOR SYSTEMATIC METABOLIC CHARACTERIZATION OF A CHEMICAL LIBRARY CONSISTING OF ~3,300 SMALL MOLECULES, COVERING MORE THAN 1,000 DRUG TARGETS. OUR PRELIMINARY RESULTS DEMONSTRATE THAT METABOLOMICS IS MORE SENSITIVE, REPRODUCIBLE, AND PREDICTIVE OF PROPERTIES OF SMALL MOLECULES, SUCH AS THE MOLECULAR TARGET, ADVERSE DRUG REACTIONS, AND CHEMICAL STRUCTURE, THAN TRANSCRIPTOMICS. FOR A D4 PLATFORM TO BE SUCCESSFULLY APPLIED, IT IS NECESSARY TO SCREEN LARGE NUMBERS OF COMPOUNDS TO COVER CHEMICAL SPACE. IN ADDITION, THESE COMPOUNDS NEED TO BE SCREENED ON MANY CELL LINES, AS DRUG PERTURBATIONS ARE OFTEN CONTEXT DEPENDENT. THE OVERALL AIM OF THIS PROPOSAL IS TO DEVELOP AN INTEGRATED WORKFLOW THAT COMBINES COMPUTATION AND EXPERIMENTATION TO EFFICIENTLY EXPAND THE METD4 DATASET. PHASE I WILL FOCUS ON A CRITICAL AND LIKELY MOST CHALLENGING PART OF THIS WORKFLOW: DEVELOPMENT OF COMPUTATIONAL METHODS TO GENERATE “VIRTUAL METABOLOMIC PROFILES” OF UNSCREENED COMPOUNDS. WE WILL 1) DEVELOP METHODS TO PREDICT METABOLIC PROFILES OF UNSCREENED CELL LINE/COMPOUND COMBINATIONS, WHICH WILL ENABLE MORE EFFICIENT SCREENING OF NEW CELL LINES BY COMBINING SPARSE SCREENING AND COMPUTATIONAL INFERENCE, 2) DEVELOP METHODS TO PREDICT METABOLOMIC DRUG PERTURBATIONS OF NOVEL COMPOUNDS BASED ON CHEMICAL STRUCTURE, 3) GENERATE METABOLOMICS DATA TO PROSPECTIVELY VALIDATE THE DEVELOPED ALGORITHMS, AND 4) DEVELOP A CONFIDENCE METRIC THAT ESTIMATES THE ACCURACY OF THE VIRTUAL METABOLOMIC PROFILES. PHASE II WILL FOCUS ON DEVELOPING STRATEGIES TO DECIDE WHICH VIRTUAL SAMPLES TO UTILIZE AND TO SELECT OPTIMAL EXPERIMENTAL SCREENING STRATEGIES TO EFFICIENTLY EXPAND THE COVERAGE OF THE METD4 DATASET BOTH IN TERMS OF CHEMICAL SPACE AND IN TERMS OF BIOLOGICAL CONTEXT. THE ITERATIVE COMPUTATIONAL AND EXPERIMENTAL WORKFLOW DEVELOPED IN PHASE II WILL ALLOW US TO EFFICIENTLY SCALE OUR PLATFORM TO: 1) SIGNIFICANTLY LARGER NUMBER OF COMPOUNDS SCREENED, 2) SIGNIFICANTLY LARGER NUMBER OF CELL LINES SCREENED FOR MORE TAILORED AND RELEVANT SCREENING FOR SPECIFIC THERAPEUTIC AREAS OF INTEREST, AND 3) SCREENING ON SYSTEMS THAT INHERENTLY HAVE LOW THROUGHPUT (E.G. TISSUES, PATIENT SAMPLES, ETC.). THESE FUNDAMENTAL IMPROVEMENTS WILL ALLOW US TO COMMERCIALIZE THE PLATFORM THROUGH INVESTMENT TO PURSUE INTERNAL DRUG DEVELOPMENT OPPORTUNITIES AND/OR THROUGH PARTNERSHIP WITH BIOTECH/PHARMA COLLABORATORS.

DEVELOPMENT AND VALIDATION OF DATA STANDARDS AND COMPUTATIONAL METHODS FOR LARGE SCALE METABOLOMICS DATA ANALYSIS FOR DATA DRIVEN DRUG DISCOVERY - PROJECT SUMMARY DATA-DRIVEN DRUG DISCOVERY (D4) IS THE COMBINED UTILIZATION OF THE PHENOTYPIC-BASED DRUG DISCOVERY PARADIGM WITH HIGH-THROUGHPUT OMICS TECHNOLOGIES AND MACHINE LEARNING. D4 HAS THE ADVANTAGE OF BEING UNBIASED, SIMILAR TO PHENOTYPIC-BASED DRUG DISCOVERY. IN ADDITION, D4 ALLOWS FOR GAINING MECHANISTIC INSIGHTS AS OMICS TECHNOLOGIES ALLOW FOR COMPREHENSIVE MEASUREMENT OF 100S TO 100,000S OF BIOMOLECULES OR CELLULAR FEATURES, WHICH ENABLES DEEP CHARACTERIZATION OF DISEASES AND COMPOUND/GENETIC PERTURBATIONS. THE PREDOMINANT DATA TYPE FOR D4 HAS HISTORICALLY BEEN TRANSCRIPTOMICS AND, MORE RECENTLY, IMAGE-BASED ASSAYS HAVE BEEN UTILIZED. OTHER BIOMOLECULAR FEATURES (I.E., PROTEINS AND METABOLITES) ARE CONSIDERED CLOSER TO THE PHENOTYPE, BUT TECHNICAL CHALLENGES IN DATA GENERATION AND ANALYSIS, AS WELL AS THE LACK OF STANDARDIZED PIPELINES HAVE PRECLUDED THE SYSTEMATIC USE OF THESE DATA TYPES. SINOPIA BIOSCIENCE AND OMIX TECHNOLOGIES HAVE COMBINED THEIR STRENGTHS IN SYSTEMS BIOLOGY DATA ANALYSIS, AI/ML, AND LC-MS/MS BASED METABOLOMICS TO DEVELOP A UNIQUE METABOLOMICS- BASED DRUG DISCOVERY PLATFORM THAT HAS ALLOWED FOR SYSTEMATIC METABOLIC CHARACTERIZATION OF A CHEMICAL LIBRARY CONSISTING OF ~3,300 SMALL MOLECULES, COVERING MORE THAN 1,000 DRUG TARGETS. OUR PRELIMINARY RESULTS DEMONSTRATE THAT METABOLOMICS IS MORE SENSITIVE, REPRODUCIBLE, AND PREDICTIVE OF PROPERTIES OF SMALL MOLECULES, SUCH AS THE MOLECULAR TARGET, ADVERSE DRUG REACTIONS, AND CHEMICAL STRUCTURE, THAN TRANSCRIPTOMICS. HOWEVER, FOR A D4 PLATFORM TO BE SUCCESSFULLY APPLIED, STANDARDIZED METHODS ARE REQUIRED TO GENERATE ROBUST AND INFORMATION- RICH PROFILES OF METABOLISM THAT CAN BE COMPARED BETWEEN EXPERIMENTS. WHEREAS FOR GENE EXPRESSION SUCH METHODS HAVE BEEN DEVELOPED AND BENCHMARKED, MULTIPLE KEY CHALLENGES REMAIN FOR METABOLOMICS DATA. IN THIS GRANT, WE WILL ADDRESS THESE CHALLENGES. WE WILL DEVELOP COMPUTATIONAL METHODS FOR GENERATING AND COMPARING PROFILES AND TEST THEM USING COMPUTATIONAL BENCHMARKING TEST CASES AND PROSPECTIVE EXPERIMENTAL VALIDATION. IN PHASE II, WE WILL EXPAND THE PLATFORM BY INCREASING THE NUMBER OF COMPOUNDS AND DISEASES PROFILED, INTEGRATE METABOLOMICS-BASED D4 WITH GENE EXPRESSION DATA, DEVELOP SOFTWARE FOR OFF-THE-SHELF APPLICATION, AND APPLY THE PLATFORM IN THE FIELDS OF ONCOLOGY AND/OR INFLAMMATION. THE PLATFORM WILL ULTIMATELY BE COMMERCIALIZED THROUGH PURSUING INTERNAL DRUG DEVELOPMENT OPPORTUNITIES AND/OR IN PARTNERSHIP WITH BIOTECH/PHARMA COLLABORATORS.

CN FARM TO SCHOOL GRANT

PRECLINICAL ASSESSMENT OF A NOVEL COMPOUND FOR TREATING RADIATION-INDUCED ORAL MUCOSITIS - PROJECT SUMMARY INFLAMMATION AND ULCERATION OF MUCOSAL TISSUE, CALLED MUCOSITIS, IS A SEVERE SIDE EFFECT OF MANY COMMON TREATMENTS IN ONCOLOGY, INCLUDING CHEMO- AND RADIOTHERAPY. MUCOSITIS DEVELOPMENT IS COSTLY TO THE HEALTH CARE SYSTEM AND CAN LEAD TO POORER OUTCOMES FOR PATIENTS. MUCOSITIS OF THE MOUTH AND ESOPHAGUS, CALLED ORAL MUCOSITIS, IS PARTICULARLY COMMON IN HEAD AND NECK CANCER PATIENTS RECEIVING RADIATION THERAPY, WHERE ROUGHLY 80% OF PATIENTS DEVELOP THIS SIDE EFFECT. TREATING ORAL MUCOSITIS REMAINS A LARGE CLINICAL UNMET NEED WITH NO FDA APPROVED TREATMENTS FOR PATIENTS WITH SOLID TUMORS. USING SINOPIA BIOSCIENCES’ COMPUTATIONAL PLATFORM, WE IDENTIFIED A UNIQUE TARGET CLASS AND AN ASSOCIATED SMALL MOLECULE FOR PREVENTING AND/OR TREATING MUCOSITIS. THE TARGET CLASS HAS AN ESTABLISHED SAFETY PROFILE IN PATIENTS WITH SOLID TUMORS. IN TWO STUDIES WITH THE ACUTE RADIATION- INDUCED HAMSTER MODEL OF ORAL MUCOSITIS, WE OBSERVED PROMISING RESULTS THAT ORAL ADMINISTRATION OF THE COMPOUND SIGNIFICANTLY DECREASED THE DURATION OF ULCERATIVE MUCOSITIS AND IN SOME ANIMALS COMPLETELY PREVENTED THE DEVELOPMENT OF ULCERS. THE OBSERVED EFFECT SIZE WAS AS LARGE OR LARGER THAN OTHER COMPOUNDS CURRENTLY IN THE CLINIC TESTED IN THE SAME MODEL. THE TEST COMPOUND IS A PAN-INHIBITOR OF SEVERAL TARGETS IN THE TARGET CLASS, EACH WITH MULTIPLE BINDING DOMAINS. IN THIS PHASE I PROPOSAL, WE WILL TEST THREE ADDITIONAL COMPOUNDS WITH DIFFERENT SELECTIVITY TO THESE TARGETS AND DOMAINS IN ORDER TO UNDERSTAND THE PHARMACOLOGY OF THIS TARGET CLASS TO DETERMINE THE TARGET THAT MOST CONTRIBUTES TO MUCOSITIS AMELIORATION. IF SUCCESSFUL, IN PHASE II OF THIS PROPOSAL WE WILL DEVELOP A NOVEL COMPOUND SELECTIVE FOR THE MOST EFFECTIVE TARGET. WE WILL THEN CHARACTERIZE THIS NEW COMPOUND IN THE FRACTIONATED RADIATION MODEL OF ORAL MUCOSITIS AND THE CHEMOTHERAPY-INDUCED GASTROINTESTINAL MUCOSITIS TO ADVANCE TOWARDS THE CLINIC.

DEVELOPMENT OF A METABOLOMICS ENABLED AI/ML PLATFORM FOR DISCOVERY OF NEW TREATMENTS TO ENHANCE DRUG SENSITIVITY IN CANCER - PROJECT SUMMARY COUPLING HIGH-THROUGHPUT OMICS TECHNOLOGIES WITH MACHINE LEARNING AND THE PHENOTYPIC-BASED DRUG DISCOVERY PARADIGM ALLOWS FOR DATA-DRIVEN DRUG DISCOVERY (D4). D4 HAS THE ADVANTAGE OF BEING UNBIASED, LIKE PHENOTYPIC- BASED DRUG DISCOVERY, BUT THE COMPREHENSIVE MEASUREMENTS OF 100S TO 100,000S OF BIOLOGICAL FEATURES ALSO ENABLES CHARACTERIZING DRUG PERTURBATIONS AND DISEASE SIGNATURES TO GAIN MECHANISTIC INSIGHTS. THE PREDOMINANT DATA TYPE FOR D4 HAS BEEN TRANSCRIPTOMICS AND MORE RECENTLY IMAGE-BASED ASSAYS. OTHER BIOMOLECULES (I.E., PROTEINS AND METABOLITES) ARE CONSIDERED CLOSER TO THE PHENOTYPE, HOWEVER TECHNICAL CHALLENGES IN DATA GENERATION AND ANALYSIS, AS WELL AS THE LACK OF STANDARDIZED DATA ANALYSIS PIPELINES HAVE LIMITED THE SYSTEMATIC USE OF THESE DATA TYPES. SINOPIA BIOSCIENCE AND OMIX TECHNOLOGIES HAVE COMBINED THEIR STRENGTHS IN SYSTEMS BIOLOGY DATA ANALYSIS, AI/ML, AND LC-MS/MS BASED METABOLOMICS TO DEVELOP A UNIQUE METABOLOMICS-BASED PLATFORM THAT HAS ALLOWED FOR SYSTEMATIC METABOLIC CHARACTERIZATION OF A CHEMICAL LIBRARY CONSISTING OF ~3,300 SMALL MOLECULES COVERING MORE THAN 1,000 DRUG TARGETS. OUR PRELIMINARY RESULTS DEMONSTRATE THAT METABOLOMICS IS MORE SENSITIVE, REPRODUCIBLE, AND PREDICTIVE OF THE MECHANISM OF ACTION OF THESE SMALL MOLECULES THAN TRANSCRIPTOMICS. FURTHER, WE FOUND THAT USING METABOLOMICS DATA WE COULD PREDICT CELL LINE SPECIFIC TOXICITY OF CANCER DRUGS IN VIABILITY ASSAYS. IMPORTANTLY, WE FOUND WE COULD DERIVE METABOLIC SIGNATURES OF SENSITIVITY AND RESISTANCE AND USE THESE TO IDENTIFY SECONDARY COMPOUNDS THAT CAN ENHANCE SENSITIVITY TO CANCER DRUGS. IN THIS PHASE I PROPOSAL, WE WILL EXPAND ON THESE FINDINGS AND DEVELOP NOVEL ALGORITHMS TO BETTER UNDERSTAND HOW BASELINE METABOLIC STATES OF CANCERS AFFECT THEIR SENSITIVITY TO CANCER DRUGS. AS A DEVELOPMENT TEST CASE WE WILL FOCUS ON SENSITIVITY OF BREAST CANCER CELL LINES TO DOCETAXEL AND TUCATINIB. FIRST, WE WILL PERFORM HIGH THROUGHPUT METABOLOMICS AND ANALYSIS OF 100 CANCER CELL LINES TO CHARACTERIZE METABOLISM BOTH IN A BASELINE STATE AND AFTER ADMINISTRATION OF DOCETAXEL AND TUCATINIB. SECOND, WE WILL DEVELOP NOVEL COMPUTATIONAL ALGORITHMS FOR PREDICTING THE ABILITY OF COMPOUNDS TO SENSITIZE CANCER CELLS TO CANCER DRUGS. FINALLY, WE WILL EXPERIMENTALLY VALIDATE NOVEL COMPOUND COMBINATIONS AND GENERATE METABOLOMICS DATA TO FURTHER IMPROVE OUR ALGORITHMS. SUCCESS OF THIS PHASE I PROPOSAL WILL LEAD TO VALIDATED METABOLOMICS-BASED METHODS FOR IDENTIFYING UNDERLYING METABOLIC PHENOTYPES PREDICTIVE OF DRUG SENSITIVITY, WHICH WILL THEN BE LEVERAGED TO PREDICT THE EFFECTS OF COMPOUND COMBINATIONS. THIS ALLOWS US TO FURTHER EXPAND SINOPIA’S PLATFORM’S CAPABILITIES AND ITS APPLICATION TO ONCOLOGY APPLICATIONS THROUGH PARTNERSHIPS WITH BIOTECH/PHARMA AND/OR FUNDRAISING THROUGH OUTSIDE INVESTORS. IN ADDITION, IT WOULD LEAD TO NOVEL USE OF TARGETS AND COMPOUNDS TO ENHANCE THE SENSITIVITY TO EXISTING CANCER TREATMENTS THAT WE CAN INTERNALLY DEVELOP. PHASE II WILL FOCUS ON FURTHER DEVELOPMENT OF THE PLATFORM, EXPANDING OUR METABOLOMICS-BASED LIBRARY, AND ADVANCING PROMISING SYNERGISTIC COMBINATIONS INTO PRECLINICAL MODELS.

STTR PHASE I: HIGH EFFICIENCY LOW NOISE DETECTORS FOR HIGH OPERATING TEMPERATURE IR CAMERAS

STTR PHASE I: FLATCAM: INEXPENSIVE, COMPACT LENSLESS CAMERAS FOR IOT APPLICATIONS

IMPROVING SAFETY AND EFFICACY OF PLATELET PATHOGEN INACTIVATION TECHNIQUES THROUGH SYSTEMS BIOLOGY

IMPROVING SAFETY AND EFFICACY OF PLATELET TRANSFUSION THROUGH SYSTEMS BIOLOGY

DEVELOPING A SYSTEMS BIOLOGY PLATFORM FOR PREDICTING DRUG TOXICITY AND SAFETY

SMALL AND MID-SIZED FARMS IN THE UNITED STATES ARE FACING SIGNIFICANT CHALLENGES IN MAINTAINING PROFITABILITY, PARTICULARLY WHEN COMPETING WITH LARGE-SCALE AGRICULTURAL OPERATIONS. THESE SMALLER FARMS OFTEN TURN TO SPECIALTY CROPS LIKE HERBS AND VEGETABLES TO DIFFERENTIATE THEMSELVES, BUT THE LABOR COSTS ASSOCIATED WITH MANUAL HARVESTING AND PACKAGING THESE CROPS CAN BE PROHIBITIVELY HIGH. THIS PROJECT AIMS TO ADDRESS THIS ISSUE BY DEVELOPING A NOVEL AUTOMATED SYSTEM FOR HARVESTING AND HANDLING LIVING HYDROPONIC BASIL. THIS DEVELOPMENT HAS POTENTIALLY REVOLUTIONIZE HOW SMALL AND MID-SIZED FARMS OPERATE AND COMPETE IN THE MARKET BY GIVING THEM ACCESS TO COST EFFECTIVE LABOR AUTOMATION.THE RESEARCH WILL FOCUS ON MODIFYING AN EXISTING AUTOMATED GREENHOUSE SYSTEM TO HARVEST LIVING BASIL PLANTS WHILE KEEPING THEIR ROOTS INTACT AND THEN PACKAGE THEM FOR WHOLESALE DISTRIBUTION. THIS APPROACH OFFERS SEVERAL ADVANTAGES OVER TRADITIONAL CUT BASIL PRODUCTION, INCLUDING REDUCED LABOR COSTS, DECREASED PACKAGING WASTE, AND A LONGER-LASTING PRODUCT FOR CONSUMERS. THE PROJECT WILL INVOLVE DESIGNING CUSTOM MECHANISMS FOR PLANT HANDLING, CREATING SPECIALIZED TRAYS AND BOXES FOR TRANSPORTATION, AND DEVELOPING SOFTWARE TO CONTROL THE ENTIRE PROCESS WITH MINIMAL HUMAN INTERVENTION.BY AUTOMATING THE HARVESTING AND PACKAGING OF LIVING BASIL, THIS PROJECT AIMS TO SIGNIFICANTLY REDUCE LABOR COSTS FOR SMALL AND MID-SIZED FARMS, POTENTIALLY INCREASING THEIR PROFITABILITY AND COMPETITIVENESS IN THE SPECIALTY CROP MARKET. THIS COULD ALSO LEAD TO MORE SUSTAINABLE FARMING PRACTICES BY REDUCING PACKAGING WASTE AND EXTENDING THE SHELF LIFE OF HERBS, WHICH IN TURN COULD DECREASE FOOD WASTE AT BOTH THE RETAIL AND CONSUMER LEVELS. ADDITIONALLY, THE SYSTEM'S COMPACT DESIGN COULD ENABLE URBAN AND PERI-URBAN FARMING, BRINGING FRESH, LOCALLY-GROWN PRODUCE CLOSER TO CONSUMERS AND POTENTIALLY REDUCING TRANSPORTATION-RELATED EMISSIONS.IF SUCCESSFUL, THIS PROJECT COULD HAVE FAR-REACHING IMPACTS ON THE AGRICULTURAL SECTOR AND BEYOND. IT COULD EMPOWER SMALL AND MID-SIZED FARMS TO ACCESS PREMIUM WHOLESALE MARKETS, POTENTIALLY LEADING TO MORE DIVERSE AND RESILIENT LOCAL FOOD SYSTEMS. THE TECHNOLOGY COULD ALSO BE ADAPTED FOR OTHER HERBS AND NURSERY CROPS, OPENING UP NEW MARKET OPPORTUNITIES FOR GROWERS. FROM A SOCIETAL PERSPECTIVE, THIS INNOVATION COULD CONTRIBUTE TO STRONGER, MORE FINANCIALLY INDEPENDENT RURAL NON-ARABLE COMMUNITIES, INCREASE ACCESS TO FRESH, LOCALLY-GROWN PRODUCE, AND SUPPORT THE GROWING TREND TOWARDS SUSTAINABLE AND EFFICIENT AGRICULTURE.ULTIMATELY, THIS PROJECT REPRESENTS A STEP TOWARDS A MORE DISTRIBUTED AND SUSTAINABLE AGRICULTURAL FUTURE, WHERE ADVANCED TECHNOLOGY IS ACCESSIBLE TO FARMS OF ALL SIZES, NOT JUST LARGE INDUSTRIAL OPERATIONS. BY LOWERING THE BARRIERS TO ENTRY FOR COMMERCIAL HERB PRODUCTION AND ENABLING MORE EFFICIENT USE OF RESOURCES, THIS RESEARCH HAS THE POTENTIAL TO CONTRIBUTE TO A MORE DIVERSE, RESILIENT, AND LOCALLY-ORIENTED FOOD SYSTEM THAT BENEFITS,PRODUCERS, CONSUMERS, AND THE ENVIRONMENT ALIKE.

IMPROVING RED BLOOD CELL TRANSFUSION THROUGH SYSTEMS BIOLOGY