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2025-05-01

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2024-05-02

2019-11-08

2023-09-25

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Department of Health and Human Services

MIRNA-NANOTECHNOLOGY AS A NOVEL REGENERATIVE THERAPY FOR LYMPHANGIOLEIOMYOMATOSIS - ABSTRACT LYMPHANGIOLEIOMYOMATOSIS (LAM) IS A TUBEROUS SCLEROSIS-RELATED DISORDER. BOTH OCCUR DUE TO AN INHERITED OR SPORADIC MUTATION IN EITHER THE TSC1 OR TSC2 GENE, WHICH FUNCTION AS NEGATIVE REGULATORS OF THE MTOR PATHWAY. UNCONTROLLED MTORC1 ACTIVITY LEADS TO THE NEOPLASTIC PROLIFERATION OF ABNORMAL SMOOTH MUSCLE CELLS (LAM CELLS) IN THE LUNGS, PROGRESSIVE SHORTNESS OF BREATH, RECURRENT PNEUMOTHORAXES, AND LOSS OF PULMONARY TISSUE STRUCTURE AND FUNCTION PRIMARILY IN WOMEN. THE FIRST AND ONLY FDA-APPROVED TREATMENT FOR LAM IS THE IMMUNOSUPPRESSANT SIROLIMUS, MARKETED SINCE 2015 BY PFIZER. IT IS THE CURRENT STANDARD-OF-CARE AND ACTS BY INHIBITING MTORC1. SIROLIMUS HAS SEVERAL CLINICAL DISADVANTAGES, INCLUDING A CONSIDERABLE NUMBER OF NON- RESPONDERS, SEVERE ADVERSE EVENTS DUE TO ITS IMMUNOSUPPRESSIVE PROPERTIES AND PREGNANCY CATEGORY C, LIMITING ITS USE IN WOMEN OF CHILDBEARING AGE. THUS, THERE IS A HIGH UNMET MEDICAL NEED TO DEVELOP ALTERNATIVE AND SAFER TREATMENT OPTIONS FOR LAM AND TS. WE HAVE IDENTIFIED TREATMENT WITH MIRNA302B MIMICS AS A POTENTIAL NOVEL THERAPY FOR LAM/TS. USING A MURINE LUNG INJURY MODEL, OUR COLLABORATOR HAO SHEN WAS ABLE TO SHOW THAT NON-TARGETED TREATMENT WITH MIRNA302B MIMICS AS NEUTRAL LIPID EMULSION IMPROVED LUNG FUNCTION, HOST RECOVERY, AND ALVEOLAR EPITHELIAL REGENERATION MICE. WE ALSO DEMONSTRATED A “STALLED” AT2-AT1 TRANSDIFFERENTIATION STATE IN HUMAN LAM, SUGGESTING THAT IMPAIRED AT2 FITNESS MAY CONTRIBUTE TO LOSS OF ALVEOLAR STRUCTURE. OUR GOAL FOR THIS GRANT IS THE INVESTIGATION OF PULMONARY-EPITHELIUM TARGETED MIRNA302B MIMIC LIPID NANOPARTICLES (LNP) EFFICACY FOR THE TREATMENT OF LAM BY ENHANCING AT2 CELL REGENERATION. AIM 1 IS COMPOSED OF IN VITRO CHARACTERIZATION OF THE MIRNA-302B MIMIC LIPID NANOPARTICLE AND INVESTIGATION OF SEVERAL TARGETING STRATEGIES IN VIVO. OUR PI DR. JAKE BRENNER WILL DESIGN AND CONSTRUCT THE NANOPARTICLES IN HIS BIOENGINEERING LAB. WE WILL PERFORM 3D ORGANOID EXPERIMENTS WITH HUMAN AND MOUSE AT2 CELLS IN THE PRESENCE OF THE LNP[MIR302B] FOLLOWED BY AN IN VIVO STUDY COMPARING DIFFERENT TARGETING STRATEGIES TO REACH THE DESIRED TISSUE AND CELL TYPE USING A TRANSGENIC MODEL OF LAM, DEVELOPED BY OUR OTHER PI PROF. VERA KRYMSKAYA. USING THE MOST EFFECTIVE TARGETING STRATEGY, AIM 2 WILL BE AN IN VIVO PROOF-OF-CONCEPT STUDY USING THAT SAME TRANSGENIC MURINE MODEL PRE AND POST-PREGNANCY TO ANSWER THE QUESTION WHETHER OUR TREATMENT WILL PREVENT AIRSPACE ENLARGEMENT AND LEAD TO LUNG RECOVERY. WE WILL OBSERVE MICE FOR 4 AND 8 WEEKS AFTER INTRATRACHEAL LNP[MIR302B] ADMINISTRATION. ENDPOINTS WILL INCLUDE LUNG FUNCTION, BALF ANALYSIS, QPCR, AND HISTOLOGICAL LUNG SECTIONS STAINED FOR THE DISEASE RELATED MARKERS AND CELL TYPES. ALL COLLABORATORS ARE EXPERTS IN THEIR RESPECTIVE FIELD AND THUS WELL EQUIPPED TO SUCCESSFULLY COMPLETE THIS PROJECT, BRINGING TOGETHER A NUMBER OF UNIQUE AND INNOVATIVE ASPECTS TO TREAT THIS DEVASTATING RARE DISEASE.

301016.00

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0.00

2023-08-31

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Department of Health and Human Services

NOVEL COMBINATION THERAPY FOR TREATMENT AND PREVENTION OF PULMONARYLYMPHANGIOLEIOMYOMATOSIS (LAM) AND TUBEROUS SCLEROSIS COMPLEX (TSC) - 1 ABSTRACT 2 TUBEROUS SCLEROSIS (TS), ALSO CALLED TUBEROUS SCLEROSIS COMPLEX, IS A RARE, MULTI-SYSTEMIC GENETIC AND OFTEN LIFE- 3 THREATENING DISEASE THAT CAUSES BENIGN TUMORS TO GROW IN THE BRAIN AND ON OTHER VITAL ORGANS SUCH AS THE KIDNEYS, 4 HEART, EYES, LUNGS, AND SKIN. LYMPHANGIOLEIOMYOMATOSIS (LAM) IS A TS-RELATED TUMOR-LIKE DISORDER. BOTH OCCUR 5 AS A CONSEQUENCE OF AN INHERITED OR SPORADIC MUTATION IN EITHER THE TSC1 OR TSC2 GENE, WHICH FUNCTION AS 6 NEGATIVE REGULATORS OF THE MTOR PATHWAY. UNCONTROLLED MTORC1 ACTIVITY LEADS TO THE NEOPLASTIC PROLIFERATION OF 7 ABNORMAL SMOOTH MUSCLE CELLS (LAM CELLS) IN THE LUNGS, PROGRESSIVE SHORTNESS OF BREATH, RECURRENT 8 PNEUMOTHORAXES, AND LOSS OF PULMONARY TISSUE STRUCTURE AND FUNCTION. IN ADDITION, PUBLISHED DATA SUGGESTS THAT 9 LAM CELLS MAY EVADE IMMUNE SURVEILLANCE BY UPREGULATING THE SURFACE EXPRESSION OF PROGRAMMED DEATH-LIGAND 1 10 (PD-L1). LAM IS A RARE DISEASE AFFECTING WOMEN IN CHILDBEARING AGE. THE FIRST AND ONLY FDA-APPROVED TREATMENT 11 FOR LAM IS THE IMMUNOSUPPRESSANT RAPAMYCIN. IT IS THE CURRENT STANDARD-OF-CARE AND ACTS BY INHIBITING MTORC1. 12 RAPAMYCIN HAS SEVERAL CLINICAL DISADVANTAGES, INCLUDING A CONSIDERABLE NUMBER OF NON-RESPONDERS, SEVERE 13 ADVERSE EVENTS DUE TO ITS IMMUNOSUPPRESSIVE PROPERTIES AND PREGNANCY CATEGORY C, LIMITING ITS USE IN WOMEN OF 14 CHILDBEARING AGE. THUS, THERE IS A HIGH UNMET MEDICAL NEED TO DEVELOP ALTERNATIVE AND SAFER TREATMENT OPTIONS FOR 15 LAM AND TS. WE HAVE IDENTIFIED ANTI-PD1 CHECKPOINT BLOCKADE AS A POTENTIAL NOVEL THERAPY FOR LAM/TS. USING 16 OUR RECENTLY DEVELOPED IMMUNOCOMPETENT MOUSE MODEL, THE CO-PI PROF. KRYMSKAYA WAS ABLE TO SHOW THAT 17 TREATMENT WITH AN ANTI-PD1 ANTIBODY SIGNIFICANTLY IMPROVED MOUSE SURIVAL. TO ADVANCE IMMUNETHERAPY FOR LAM, 18 OUR GOAL FOR THIS GRANT IS THE INVESTIGATION OF THE MECHANISTIC INTERPLAY BETWEEN RAPAMYIN AND ANTI-PD1 ANTIBODIES 19 TO HARNESS THE POTENTIAL OF A COMBINATION THERAPY IN VITRO AND IN VIVO. AIM 1 WILL COVER A SET OF IN VITRO STUDIES, 20 INVESTIGATING IMMUNE-RELEVANT EXPRESSION PATTERNS AND UNDERLYING CELLULAR EFFECTS ON MTOR AND RELATED SIGNALING 21 PATHWAYS, SINCE THE RELATIONSHIP BETWEEN THE FORMER AND CHECKPOINT BLOCKADE IS NOT FULLY UNDERSTOOD YET. WE WILL 22 USE IMMORTALIZED TSC2-NULL 101, 102 AND TSC2-EXPRESSING 103 CELLS BEFORE MOVING ON TO OUR EXPANDED LIBRARY 23 OF PRIMARY HUMAN LAM-DERIVED AML (LAMD) CELLS, ORIGINATING FROM OVER 25 LAM PATIENTS. INVESTIGATING THE EFFECT 24 OF RAPAMYCIN AND MTOR/AKT SIGNALLING WILL INCREASE OUR UNDERSTANDING OF THE CONNECTION BETWEEN THOSE PATHWAYS 25 AND PD-L1 UPREGULATION, BEFORE MOVING ON TO AIM 2. THE IN VIVO PROOF OF CONCEPT WILL COMPARE PREVENTATIVE AND 26 THERAPEUTIC CO-TREATMENT WITH ANTI-PD1 AND RAPAMYING IN AN IMMUNOCOMPETENT TSC2-NULL MURINE MODEL 27 DEVELOPED AT THE LABORATORY OF PROF. KRYMSKAYA AT THE UNIVERSITY OF PENNSYLVANIA. WE WILL EVALUATE PREVENTION OF 28 TSC2-NULL LESION GROWTH, IMMUNOHISTOCHEMICAL AND LUNG MORPHOLOGY CHANGES AND ANIMAL SURVIVAL. THIS PROJECT 29 AIMS TO DEVELOP A NOVEL THERAPY FOR PATIENTS WITH THE DEVASTATING DISEASES OF LAM/TS. BASED ON PEMBROLIZUMAB’S 30 FAVORABLE SAFETY PROFILE IN ITS APPROVED INDICATIONS, POSITIVE EFFICACY RESULTS IN OUR STUDIES WOULD ENABLE AN 31 ACCELERATED CLINICAL DEVELOPMENT UNDER FDA BPIC ACT FOR BIOLOGICS AND ORPHAN DISEASE DESIGNATION FOR LAM/TS. 32

299997.00

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2021-04-09

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Department of Health and Human Services

NITAZOXANIDE AS A NOVEL THERAPY FOR RARE DISEASE LYMPHANGIOLEIOMYOMATOSIS AND TUBEROUS SCLEROSIS - ABSTRACT TUBEROUS SCLEROSIS (TS), ALSO CALLED TUBEROUS SCLEROSIS COMPLEX, IS A RARE, MULTI-SYSTEMIC GENETIC AND OFTEN LIFE- THREATENING DISEASE THAT CAUSES BENIGN TUMORS TO GROW IN THE BRAIN AND ON OTHER VITAL ORGANS SUCH AS THE KIDNEYS, HEART, EYES, LUNGS, AND SKIN. LYMPHANGIOLEIOMYOMATOSIS (LAM) IS A TS-RELATED TUMOR-LIKE DISORDER. BOTH OCCUR AS A CONSEQUENCE OF AN INHERITED OR SPORADIC MUTATION IN EITHER THE TSC1 OR TSC2 GENE, WHICH FUNCTION AS NEGATIVE REGULATORS OF THE MTOR PATHWAY. UNCONTROLLED MTORC1 ACTIVITY LEADS TO THE NEOPLASTIC PROLIFERATION OF ABNORMAL SMOOTH MUSCLE CELLS (LAM CELLS) IN THE LUNGS, PROGRESSIVE SHORTNESS OF BREATH, RECURRENT PNEUMOTHORAXES, AND LOSS OF PULMONARY TISSUE STRUCTURE AND FUNCTION. TS AFFECTS AS MANY AS 25,000 TO 40,000 INDIVIDUALS IN THE UNITED STATES AND ABOUT 1 TO 2 MILLION INDIVIDUALS WORLDWIDE. LAM IS A RARE DISEASE AFFECTING WOMEN IN CHILDBEARING AGE. THE FIRST AND ONLY FDA-APPROVED TREATMENT FOR LAM IS THE IMMUNOSUPPRESSANT SIROLIMUS (RAPAMUNE©), MARKETED SINCE 2015 BY PFIZER. IT IS THE CURRENT STANDARD-OF-CARE AND ACTS BY INHIBITING MTORC1. SIROLIMUS HAS SEVERAL CLINICAL DISADVANTAGES, INCLUDING A CONSIDERABLE NUMBER OF NON-RESPONDERS, SEVERE ADVERSE EVENTS DUE TO ITS IMMUNOSUPPRESSIVE PROPERTIES AND PREGNANCY CATEGORY C, LIMITING ITS USE IN WOMEN OF CHILDBEARING AGE. THUS, THERE IS A HIGH UNMET MEDICAL NEED TO DEVELOP ALTERNATIVE AND SAFER TREATMENT OPTIONS FOR LAM AND TS. WE HAVE IDENTIFIED NITAZOXANIDE (HEREAFTER NTZ; ALINIA©), AN ANTIPROTOZOAL FDA-APPROVED AND SAFE THERAPY FOR THE TREATMENT OF DIARRHEA CAUSED BY GIARDIA LAMBLIA OR CRYPTOSPORIDIUM PARVUM IN PATIENTS 1 YEAR OF AGE OR OLDER, AS A POTENTIAL NOVEL THERAPY FOR LAM/TS. USING CAPTURE COMPOUND MASS SPECTROMETRY TECHNOLOGY, WE DISCOVERED NAD(P)H QUINONE OXIDOREDUCTASE (NQO1) AS THE HUMAN TARGET OF NITAZOXANIDE. FURTHERMORE, WE HAVE SHOWN THAT NTZ IS EFFECTIVE IN INHIBITING MTORC1 RELATED CELLULAR SIGNALING IN THREE DIFFERENT LAM RELATED MURINE AND HUMAN CELL LINES ADDRESSING THE UNDERLYING PATHOLOGICAL MECHANISM OF LAM/TS. OUR GOAL FOR THIS GRANT IS THE INVESTIGATION OF NTZ’S EFFICACY FOR THE TREATMENT OF LAM/TS. AIM 1 WILL BE THE IN VIVO PROOF OF CONCEPT COMPARING THREE DOSE LEVELS OF NTZ IN A TSC2-NULL MURINE MODEL DEVELOPED AT THE LABORATORY OF PROF. KRYMSKAYA AT THE UNIVERSITY OF PENNSYLVANIA. IT WILL EVALUATE PREVENTION OF TSC2-NULL LESION GROWTH, IMMUNOHISTOCHEMICAL AND LUNG MORPHOLOGY CHANGES AND ANIMAL SURVIVAL IN A MURINE LAM MODEL. AIM 2 WILL COVER AN IN VITRO STUDY, INVESTIGATING UNDERLYING CELLULAR EFFECTS ON MTOR AND RELATED SIGNALING PATHWAYS. THE IN VITRO STUDY WILL INVESTIGATE NTZ'S EFFECTS IN LAM-DERIVED AML (LAMD) CELLS AND IMMORTALIZED TSC2-NULL CELL CULTURES OF HUMAN ORIGIN FOLLOWED BY MORE DETAILED MTORC1 INTERACTIONS STUDIES. IN ADDITION TO THE MONOTHERAPEUTIC NTZ APPROACH, DOSE REDUCTION POTENTIAL FOR DOSE-TOXICITY PRONE RAPAMYCINE WITH NTZ ADD-ON WILL BE EXPLORED. THIS PROJECT AIMS TO DEVELOP A NOVEL THERAPY FOR PATIENTS WITH THE DEVASTATING DISEASES OF LAM/TS. BASED ON NTZ'S EXCELLENT SAFETY PROFILE AS AN APPROVED ANTIPROTOZOAL DRUG, POSITIVE EFFICACY RESULTS IN OUR STUDIES WOULD ENABLE AN ACCELERATED CLINICAL DEVELOPMENT UNDER FDA SECTION 505 (2)(B) APPROVAL PATHWAY AND ORPHAN DISEASE DESIGNATION.

256400.00

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