This $600,475 federal Project Grant award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846) aims to develop a collagen-based scaffold modified with specific integrin ligands and placental mesenchymal stem cell-derived extracellular vesicles. This engineered scaffold is intended to synergistically recruit and guide endogenous stem cells for vascularized bone regeneration in...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research program (CFDA 93.837), provides $2,654,903 to The Children's Hospital Corporation (Boston Children's Hospital) to develop a novel viral particle technology platform for in vivo and ex vivo delivery of genetic therapies to hematopoietic stem cells (HSCs). The primary objectives of this 4-year project are to: (1) develop integrating vectors to deliver a curative...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research program (CFDA 93.837), provides $734,607 to Boston Medical Center Corporation to conduct research on the mechanisms that regulate the migration of hematopoietic stem cells (HSCs) into their bone marrow niches. The goal is to elucidate the key endothelial cell adhesion and vesicle trafficking processes that facilitate the extravasation of HSCs, in order to...
This $546,600 Project Grant awarded by the National Science Foundation's (NSF) Integrative Activities program (CFDA 47.083) aims to engineer mesenchymal stem cell-derived exosomes (MSC-EXO) for targeted immunomodulation and enhanced bone repair. The University of Maryland Eastern Shore (UMES), a historically black, 1890 land-grant institution, is the primary awardee. The key objectives of this 3-year project are to: 1) generate engineered exosomes (TEX) for reprogramming macrophages, 2) modify...
This Project Grant from the National Heart, Lung and Blood Institute, part of the Department of Health and Human Services, provides $914,900 to Ship Of Theseus LLC under the Cardiovascular Diseases Research program (CFDA 93.837). The funding supports preclinical development of a nuclear-targeting biologic to safely increase stem cell expansion in vivo and accelerate recovery from neutropenia following chemotherapy and bone marrow transplant. Specifically, the grant will advance a patented mutant...
This $159,512 Project Grant awarded by the National Heart Lung and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) supports research to generate a comprehensive single-cell transcriptomic and epigenomic map of human bone marrow cells. The goal is to establish the mesenchymal cell hierarchy in human bone and elucidate how cell fates are regulated and cell-cell interactions support cell fate decisions. The grant enables the principal investigator at the University of Pennsylvania to...
This Project Grant award from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training Program (CFDA 93.859) provides $364,167 to Villanova University to develop novel non-viral gene delivery methods for cell therapies. The key objectives are: The Bracaglia Lab will develop new polymeric gene delivery vehicles to improve the delivery of siRNAs and other payloads to T cells and hematopoietic stem cells (HSCs). Drs. Elmer and Huang will...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), part of the Cardiovascular Diseases Research program (CFDA 93.837), provides $300,000 to Gigamune, Inc. to develop an in vivo gene therapy for sickle cell disease. The project aims to test a novel lentiviral vector technology for efficiently editing hematopoietic stem cells to knockout the BCL11A enhancer, a key genetic target for sickle cell treatment. Through in vitro assays, the Phase I effort will...
This $225,306 Project Grant award from the National Science Foundation (NSF) Biological Sciences program (CFDA 47.074) supports a collaborative research project between researchers at the University of Southern California (USC) and a German partner to investigate the long-term impact of early-life growth signals on adult hematopoietic (blood) stem cell function and selection. The key products and services to be delivered under this 3-year award include: 1) using stem cell transplantation and...
This three-year, $1 million Project Grant from the National Science Foundation's Biological Sciences program (CFDA 47.074) supports the development of viral vectors for gene delivery and manipulation in amphibian research. The Trustees of Columbia University will lead efforts to design new viral vectors with host specificity for amphibians. Researchers at Columbia, the Institute of Science and Technology Austria, the University of Utah, and the Scripps Research Institute will collaborate to test...
A NOVEL APPROACH TO MESENCHYMAL STEM CELL TRANSDUCTION - PROJECT SUMMARY MESENCHYMAL STEM CELLS (MSC) ARE IN CLINICAL DEVELOPMENT FOR CARDIOVASCULAR, NEUROLOGIC, ORTHOPEDIC, AND OTHER INDICATIONS. OSSIUM IS DEVELOPING A NOVEL SOURCE OF MSC FROM VERTEBRAL BODIES (VBMSC). GENETIC MODIFICATION OF VBMSC USING LENTIVIRAL VECTOR (LV) HAS THE POTENTIAL TO IMPROVE THE THERAPEUTIC POTENTIAL. UNDERSTANDING HOW GENETIC MODIFICATION MIGHT ALTER THE VBMSC PHENOTYPE WILL BE CRITICAL TO ENSURING LV DO NOT INITIATE PREMATURE SENESCENCE OR DIMINISH THEIR THERAPEUTIC PROPERTIES. MOREOVER, AN IMPORTANT SAFETY AND REGULATORY BARRIER TO CLINICAL IMPLEMENTATION OF GENE MODIFIED VBMSC WILL BE ESTIMATING THE RISK OF INSERTIONAL MUTAGENESIS. GAMMARETROVIRAL VECTORS USED TO MODIFY HEMATOPOIETIC STEM CELLS (HSC) LED TO LEUKEMIA IN AT LEAST 4 CLINICAL TRIALS. WHILE LENTIVIRAL VECTORS APPEAR SAFER, CLONAL EXPANSION OF HSC AND MATURE T CELLS HAVE NOW BEEN REPORTED. OSSIUM SEEKS TO ADDRESS IMPORTANT SAFETY AND EFFICACY ISSUES IN THIS PHASE I PROPOSAL. WE HYPOTHESIZE THAT (1) A HIV-1 BASED LV PSEUDOTYPED WITH A NOVEL FOAMY VIRAL ENVELOPE (LV-FV) WILL EFFICIENTLY TRANSDUCE VBMSC WITH LESS CHANGE IN CELL PHENOTYPE COMPARED TO LV PSEUDOTYPED WITH VSV-G; (2), THE LV INTEGRATION PATTERN, DISTRIBUTION AMONG CANCER ASSOCIATED GENES AND ABILITY TO INDUCE CELL IMMORTALIZATION, WILL BE SIMILAR TO THAT SEEN IN OTHER CELL TYPES. TO STUDY THIS, WE PROPOSE: SPECIFIC AIM 1: ASSESS THE EFFECT OF LV GENE TRANSFER AND VECTOR PSEUDOTYPE ON VBMSC PHENOTYPE. LV EXPRESSING GREEN FLUORESCENT PROTEIN (GFP) PSEUDOTYPED WITH VSVG AND FV WILL BE USED TO TRANSDUCE VBMSC. CELLS WILL BE ASSESSED FOR GENE TRANSFER (VECTOR COPY NUMBER) AND EXPRESSION (GFP BY FLOW CYTOMETRY), VIABILITY, EXPANSION CAPACITY, MSC-ASSOCIATED SURFACE MARKERS, SECRETOME, AND ABILITY TO DIFFERENTIATE INTO THREE LINEAGES (BONE, ADIPOSE AND CARTILAGE). SPECIFIC AIM 2: EVALUATE INSERTIONAL MUTAGENESIS RISK IN LV TRANSDUCED VBMSC. THIS AIM SEEKS TO INVESTIGATE THE GENOTOXICITY OF LV VECTORS IN MSC. SPECIFIC AIM 2A. EVALUATING LV-TRANSDUCED VBMSC FOR INTEGRATION PATTERN AND CANCER-ASSOCIATED GENE PREFERENCES. COMPARISONS BETWEEN LV AND GAMMARETROVIRAL VECTORS IN LOW AND HIGH PASSAGE VBMSC WILL BE COMPARED TO PUBLISHED DATA ON HSC INTEGRATIONS. SPECIFIC AIM 2B. EVALUATING LV-TRANSDUCED VBMSC FOR IMMORTALIZATION. IN THIS SUB-AIM WE WILL SEEK TO DEVELOP AN ASSAY FOR ASSESSING IM RISK BY EVALUATING VBMSC AFTER GENE TRANSFER. THE FINDINGS WILL HAVE BROAD APPLICABILITY GIVEN THE NUMBER OF DISEASE STATES IN WHICH MSC MAY PLAY A THERAPEUTIC ROLE. THIS PROPOSAL ALSO USES A VARIETY OF INNOVATIVE TECHNOLOGIES, INCLUDING A NOVEL LV-FV, A NOVEL STEM CELL SOURCE (VERTEBRAL BODY MSC), AND WILL BE THE FIRST STUDY AIMED AT ASSESSING THE RISK OF IMMORTALIZATION IN MSC.