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AN ULTRASENSITIVE, HIGH-THROUGHPUT, AND LOW-COST AUTOIMMUNITY PANEL FOR THE EARLY DIAGNOSIS AND IMPROVED TREATMENT OF TYPE 1 DIABETES

TESTING SCALE MODELS FOR HEALTHY AND AFFORDABLE FLOORING

MULTIPLEX FOOD ALLERGY DIAGNOSTIC BASED ON IGE IMMUNOLOGIC MARKERS

DEVELOPMENT OF AN AUTOMATED HIGH-THROUGHPUT DRIED BLOOD SPOT ASSAY TO FACILITATE LARGE SCALE SCREENING FOR TYPE 1 DIABETES RISK

SOLID-STATE FABRICATION OF NANO-STRUCTURED OXIDE DISPERSION STRENGTHENED 14YWT STEEL FOR ADVANCED NUCLEAR APPLICATIONS

SBIR PHASE II: DEVELOPMENT OF AN ULTRASENSITIVE, HIGH-THROUGHPUT AUTOANTIBODY DISCOVERY PLATFORM USING AGGLUTINATION-PCR

CONGRESSIONL EARMARK

CONGRESSIONL EARMARK

CONGRESSIONAL EARMARKS

VAL-0914 DECREASES PAO TO PROTECT AGAINST CARDIAC PROTEINOPATHIES - PROJECT SUMMARY SOLUBLE PRE-AMYLOID OLIGOMERS (PAO) ARE THE MOST POTENT MEDIATORS OF CYTOTOXICITY, DESPITE COMMON FOCUS ON AUTOPHAGY AS A MEANS TO CLEAR LARGER MISFOLDED PROTEIN AGGREGATES. SPECIFICALLY, PAO, RATHER THAN AGGRESOMES, ARE MOST CORRELATED WITH DESMIN-RELATED CARDIOMYOPATHY (DRC) CAUSED BY AN ARG120GLY MISSENSE MUTATION OF AB-CRYSTALLIN (CRYABR120G). IN ADDITION TO CAUSING DRC, EMERGING EVIDENCE SUGGESTS THAT INCREASED PAO AND RESULTING PROTEOTOXIC STRESS PLAY AN IMPORTANT ROLE IN THE PROGRESSION FROM A LARGE SUBSET OF HEART DISEASES TO HEART FAILURE, A COMMON CONDITION IN THE UNITED STATES. DESPITE SUBSTANTIAL PROGRESS IN OUR UNDERSTANDING OF PAO AND RELATED DISEASES, NO EXPERIMENTAL THERAPEUTICS EXIST THAT CLEAR THESE TOXIC SPECIES FROM THE CYTOPLASM. NOTABLY, A RECENT STUDY DEMONSTRATED THAT UP-REGULATION OF MYOCARDIAL NEPRILYSIN (NEP) PROTEIN LEVELS WAS IMPLICATED AS A MAJOR MEDIATOR FOR VOLUNTARY EXERCISE TO REDUCE MISFOLDED CYTOTOXIC PROTEIN LEVELS AND SLOW DOWN DISEASE PROGRESSION IN A MODEL OF DRC. TREATMENT OF CARDIAC PROTEINOPATHIES SUCH AS DRC BY INCREASING CARDIAC NEP LEVELS TO REDUCE PAO LEVELS APPEARS TO BE A PROMISING THERAPEUTIC STRATEGY. IN ORDER TO DELIVER NEP TO THE CYTOPLASM OF HEART MUSCLE CELLS, VALERION THERAPEUTICS USES A COMMERCIALIZABLE CELL-PENETRATING 3E10 ANTIBODY FAB FRAGMENT THAT IS UNIQUELY CAPABLE OF DELIVERING FULL-LENGTH PROTEIN CARGO TO THE CYTOPLASM. 3E10 GAINS ENTRY TO THE CELLS VIA THE EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 2 (ENT2; SLC29A2), A RECEPTOR FOUND IN MANY CELL TYPES BUT IS HIGHLY EXPRESSED IN SKELETAL AND CARDIAC MUSCLE. WE ARE CURRENTLY TESTING SEVERAL FAB FUSIONS, INCLUDING FAB-GAA (VAL-1221) THAT RECENTLY DEMONSTRATED POSITIVE PHASE 1 CLINICAL RESULTS IN POMPE DISEASE (NCT02898753). VALERION HAS RECENTLY DEVELOPED A NEW FAB FUSION PROTEIN WITH NEP (VAL- 0914) THAT IS UNIQUELY CAPABLE OF PENETRATING CELLS AND DEGRADES OVEREXPRESSED CYTOPLASMIC BETA-AMYLOID(1-42). THEREFORE, VAL-0914 PRESENTS AN INNOVATIVE THERAPEUTIC STRATEGY TO TREAT CARDIAC PROTEINOPATHIES SUCH AS DESMIN-RELATED CARDIOMYOPATHY BY DELIVERING ACTIVE NEP TO THE CYTOPLASM OF AFFECTED CELLS. THE PROPOSED RESEARCH IN PHASE I WILL FOCUS ON (AIM 1) IN VITRO CHARACTERIZATION OF VAL-0914 IN CULTURED CARDIOMYOCYTE AND MOUSE HEART MODELS OF CARDIAC PROTEINOPATHY TO ESTABLISH MECHANISTIC PROOF-OF-CONCEPT AND (AIM 2) IN VIVO CHARACTERIZATION OF VAL-0914 EFFECTS ON HEART FUNCTION AND MISFOLDED PROTEIN CLEARANCE IN A MOUSE MODEL OF CARDIAC PROTEINOPATHY TO ESTABLISH PRECLINICAL MODELS FOR SUBSEQUENT IND-ENABLING PHASE II STUDIES. A SUCCESSFUL OUTCOME OF THIS WORK WILL CREATE AN IMMEDIATE ACTIONABLE IMPACT ON UNDERSERVED CARDIAC PROTEINOPATHY PATIENT POPULATIONS SUCH AS THOSE WITH DRC AND A SUBSET OF HEART FAILURE PATIENTS.

SBIR PHASE I: ANTIBODY THERAPY THAT TARGETS NEOANTIGENS IN ACUTE MYELOID LEUKEMIA VIA THE ANTIBODY DEPENDENT CELL-MEDIATED CYTOTOXICITY MECHANISM OF NATURAL KILLER CELLS -THE BROADER IMPACT/COMMERCIAL POTENTIAL OF THIS SMALL BUSINESS INNOVATION RESEARCH (SBIR) PHASE I PROJECT FOCUSES ON THE UNIQUE COMBINATION OF CANCER-SPECIFIC ANTIBODIES AND ADOPTIVE NATURAL KILLER (NK) IMMUNE CELLS NEEDED TO OFFER PERSONALIZABLE CANCER THERAPIES. THIS INNOVATION REPRESENTS A PLATFORM TECHNOLOGY THAT CAN SPAWN MULTIPLE INNOVATIVE CANCER TREATMENTS, WHICH COULD POSITIVELY IMPACT LIFE SCIENCES INNOVATION AND, MORE IMPORTANTLY, ADVANCE THE HEALTH AND WELFARE OF THE GLOBAL CANCER POPULATION. THIS NOVEL APPROACH TO IMMUNOTHERAPY OF CANCER IS EXPECTED TO BE HIGHLY EFFICACIOUS AND, DUE TO THE SPECIFICITY OF ITS MECHANISM OF ACTION, VIRTUALLY DEVOID OF TOXICITY. THIS IS SIGNIFICANT IN LIGHT OF THE FACT THAT THE NATIONAL COST OF CANCER CARE IS IN THE $200 BILLION RANGE. THIS PROJECT SEEKS TO PROVIDE A UNIQUE COMBINATION OF CANCER-SPECIFIC ANTIBODIES AND ADOPTIVE NATURAL KILLER (NK) IMMUNE CELLS THAT SYNERGIZE TO ACHIEVE HIGH EFFICACY, AVOID TOXICITY TO HEALTHY CELLS, AND OFFER A SCALABLE, RESOURCE-EFFICIENT AND PERSONALIZABLE THERAPY FOR CANCER. THE PROJECT FOCUS IS ANTIBODY TARGETING OF A NEOANTIGEN FOUND EXCLUSIVELY IN DISEASED ACUTE MYELOID LEUKEMIA (AML) CANCER CELLS, IN ORDER TO DEVELOP AN EFFECTIVE TREATMENT FOR RELAPSED / REFRACTORY DISEASE. THE 30-50 CANDIDATE ANTIBODIES WILL BE GENERATED AND TESTED BY FIRST IMMUNIZING RATS, ISOLATING THE RESULTING ANTIGEN-SPECIFIC B CELLS USING A SPECIALIZED FLUORESCENCE-ACTIVATED CELL SORTING TECHNIQUE, SEQUENCING AND CLONING THE ANTIBODY GENES, AND EXPRESSING THE ANTIBODIES IN PRODUCER CELLS. CANDIDATE ANTIBODIES WILL BE TESTED FOR SPECIFICITY (ENZYME-LINKED IMMUNOSORBENT ASSAY) AND BINDING STRENGTH (SURFACE PLASMON RESONANCE) FOR THE NEOANTIGEN TARGET, WHITTLING DOWN THE LIST TO ~15 CANDIDATE ANTIBODIES. FURTHER SCREENING WILL BE ACHIEVED BY EVALUATING ANTIBODY INDUCTION OF AML CELL-SPECIFIC KILLING BY NK CELLS; READOUTS WILL INCLUDE AML TARGET CELL DEATH MEASURED BY FLOW CYTOMETRY AND LACTATE DEHYDROGENASE RELEASE, DEGRANULATION BY NK CELLS (INDICATING KILLING ACTIVITY), AND CYTOKINE RELEASE. THE TOP-PERFORMING 3-5 CANDIDATES WILL EVENTUALLY BE SELECTED FOR PRECLINICAL TESTING. 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.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

SBIR PHASE I: DEVELOPMENT OF AN ULTRASENSITIVE, HIGH-THROUGHPUT AUTOANTIBODY DISCOVERY PLATFORM USING AGGLUTINATION-PCR

SBIR PHASE I: ANTIBODY-ENZYME FUSION FOR THE TREATMENT OF MYOTUBULAR MYOPATHY

ROSS PH SVC COORDINATOR

ANTIBODY-DETECTION-BY-AGGLUTINATION-PCR (ADAP): AN ULTRA-SENSITIVE, HIGH-THROUGHPUT, MULTIPLEXABLE TOOL FOR T1D DIAGNOSIS AND MONITORING

EARLY AND ACCURATE DIFFERENTIAL DIAGNOSIS OF LYME AND OTHER TICK-BORNE DISEASES BY AGGLUTINATION-PCR

A NOVEL SERUM ALTERNATIVE FOR EX-VIVO EXPANSION OF NATURAL KILLER CELLS FOR IMMUNOTHERAPY

MULTIPLEX FOOD ALLERGY DIAGNOSTIC BASED ON IGE IMMUNOLOGIC MARKERS

SYNTHESIS AND DIRECT MANUFACTURING OF HIGH CONDUCTIVITY ALUMINUM ALLOY CONDUCTORS USING AN ENERGY EFFICIENT SOLID-STATE PROCESS AND THEIR ADVANCED CHARACTERIZATION

HEALTHY FLOORS SCALE-UP

RESIDENT OPPORTUNITY AND SUPPORTIVE SERVICES - SERVICE COORDINATORS

RESIDENT OPPORTUNITY AND SUPPORTIVE SERVICES - SERVICE COORDINATORS

SEC 9007 REAP-RENEW ENERGY SYSTEMS GRANTS, $20,000 OR LESS (MAN)

PURPOSE: TO SUPPORT A RESIDENCY FOR ARTISTS WITH DISABILITIES.

PURPOSE: TO SUPPORT A SERIES OF FREE FAMILY-FRIENDLY VISUAL ART WORKSHOPS.

STROKE PREVENTION THROUGH ATRIAL APPENDAGE OCCLUSION