Not listed
THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER'S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.
$0 10/17/24 Not listed
THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER'S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.
$1.4m 6/21/24 Not listed
THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER'S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.
$1.4m 6/21/24 Not listed
THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER'S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.
$0 10/13/23 Not listed
THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER'S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.
$0 10/13/23