Abstract: Disclosed are compositions and methods of treating muscular dystrophies, including Duchenne Muscular Dystrophy (DMD) through administration of fibroblasts and modified fibroblasts systemically and locally. In certain embodiments, fibroblast cells are utilized for replacement of dystrophin through fusion and/or other means of horizontal gene transfer. In other embodiments, the disclosure teaches the use of fibroblasts for reduction of inflammatory reactions and/or immunological reactions which propagate and enhance myodestructive aspects of Duchenne Muscular Dystrophy. In other embodiments, fibroblasts are utilized as vectors for gene therapy and/or gene modifications approaches.

Abstract: Embodiments of the disclosure encompass methods and compositions for treatment of cancer utilizing fibroblasts that have been modified to enhance their ability to deliver one or more anti-cancer agents to an individual in need thereof. In particular embodiments, the fibroblasts have been modified to express one or more chemokine receptors and/or have been exposed to hypoxia to enhance their ability to home to cancer cells. In specific cases the modified fibroblasts are engineered to encompass an oncolytic virus as a tumor inhibitory agent.

Abstract: Embodiments of the disclosure encompass methods and compositions for treatment of cancer utilizing fibroblasts that have been modified to enhance their ability to deliver one or more anti-cancer agents to an individual in need thereof. In particular embodiments, the fibroblasts have been modified to express one or more chemokine receptors and/or have been exposed to hypoxia to enhance their ability to home to cancer cells. In specific cases the modified fibroblasts are engineered to encompass an oncolytic virus as a tumor inhibitory agent.

Abstract: The present disclosure provides means of regenerating/restoring aged and/or damaged tissue or treating a medical condition by providing an extracorporeal circuit containing cells, including fibroblasts or dedifferentiated fibroblasts. that are in contact with plasma but not blood cells extracorporeally in a manner allowing for exchange of factors between a subject and an extracorporeally residing mass of cells. The disclosure provides means of titrating factors produced by the extracorporeal regenerative cell mass, thus allowing for a regenerative effect.

Abstract: The present disclosure concerns methods and compositions for treating or preventing or reducing the risk of having Amyotrophic Lateral Sclerosis (ALS) in an individual. In particular embodiments, there are methods and compositions related to administering to the individual a therapeutically effective amount of a population of fibroblasts, fibroblast exosomes, IL-2, or a combination thereof.

Abstract: Disclosed are methods, means, and compositions of matter useful for the stimulation of angiogenesis directly by administration of membrane vesicles, such as fibroblast-derived exosomes, and/or through induction of angiogenic cytokines from blood cells contacted with fibroblast-derived exosomes. The invention provides means of treating conditions in which angiogenesis is beneficial through local or systemic administration of exosomes, including those derived from fibroblasts, wherein the fibroblasts are cultured under basal conditions or conditions of hypoxia. In other embodiments exosomes derived from fibroblasts are utilized to augment endogenous regenerative processes, such as hematopoiesis, angiogenesis and neurogenesis, as well as augment regenerative processes stimulated by administration of exogenous therapeutics such as cells, growth factors, or genes.

Abstract: Embodiments of the disclosure include methods and compositions for use of prepared fibroblasts and/or conditioned media therefrom. In particular embodiments, the prepared fibroblasts have enhanced regenerative and may have an increase in secretion of one or more cytokines and/or growth factors; may have an increase in anti-apoptotic activity; and/or may have a modulated immunogenicity. In specific embodiments, the fibroblasts are prepared by exposure to hypoxia and/or carbon monoxide.

Abstract: Embodiments of the disclosure include methods and compositions for treatment of lung disease, including at least chronic obstructive pulmonary disease (COPD). In particular cases, fibroblasts (including activated fibroblasts) and/or exosomes thereof are provided to an individual for the treatment of COPD. In particular cases the fibroblasts are activated and/or express one or more particular markers.

Abstract: Disclosed are compositions of matter and therapeutic means for increasing efficacy of immunotherapy such as Tumor Infiltrating Lymphocytes (TILs), Chimeric Antigen Receptor (CAR)-T cells, and other cellular therapies in solid tumors. In one embodiment agents capable of increasing tumor immunogenicity and/or antigen presentation by modulation of tumor stromal cells such as monocytes and pericytes are administered prior to providing immunotherapy in a patient. In some embodiments administration of interleukin-33 together with one or more antioxidants is provided as a means of stimulating expression of HLA and TAP proteins without inducing significant inflammatory response and myeloid derived suppressor cell activation in cancer associated monocytes. In other embodiments the use of histone deacetylase (HDAC) inhibitors together with interferon alpha is disclosed as a means of stimulating the expression of immunogenic molecules on monocytes to increase immunotherapy cell activity.

Abstract: Embodiments of the disclosure include methods and compositions for treatment of lung disease, including at least chronic obstructive pulmonary disease (COPD). In particular cases, fibroblasts (including activated fibroblasts) and/or exosomes thereof are provided to an individual for the treatment of COPD. In particular cases the fibroblasts are activated and/or express one or more particular markers.

Abstract: Disclosed herein are methods and compositions for treatment and prevention of alopecia, including alopecia areata. Aspects are directed to methods for stimulating or accelerating hair follicle regeneration. Certain aspects are directed to methods for treating alopecia areata comprising administration of fibroblasts and/or a fibroblast derived product to a subject suffering from alopecia areata. In some cases, a fibroblast derived product is conditioned media, exosomes, or apoptotic bodies from fibroblasts, formulated for topical use for treatment or prevention of alopecia areata.

Abstract: Embodiments of the disclosure include methods and compositions for use of prepared fibroblasts and/or conditioned media therefrom. In particular embodiments, the prepared fibroblasts have enhanced regenerative and may have an increase in secretion of one or more cytokines and/or growth factors; may have an increase in anti-apoptotic activity; and/or may have a modulated immunogenicity. In specific embodiments, the fibroblasts are prepared by exposure to hypoxia and/or carbon monoxide.

Abstract: Disclosed are novel means of enhancing efficacy of pancreatic islet transplantation through administration of regenerative T cells concurrently with modification of the local microenvironment to provide a tolerogenic and angiogenic milieu. In one embodiment, the liver microenvironment is prepared for receipt of pancreatic islets by administration of tolerogenic cells antigen presenting cells, subsequently followed by administration of T cells and/or T regulatory cells conditioned by regenerative cells, and finally pancreatic islets are administered. In other embodiments devices are provided which allow for concurrent administration of pancreatic islets together with T cells and/or T regulatory cells that have been conditioned with regenerative cells. In another embodiment, the administration of T cells and/or T regulatory cells conditioned by regenerative cells is after administration of therapeutic pancreatic islets.

Abstract: Disclosed are means, compounds, and compositions of matter useful for stimulation of natural killer cell activity. On one embodiment a composition termed QuadraMune™ comprised of pterostilbene, Nigella sativa extract, green tea extract, and broccoli. In some embodiments the invention teaches the administration of a therapeutic combination of ingredients comprising of metformin, pterostilbene, Nigella sativa, sulforaphane, and epigallocatechin-3-gallate (EGCG) to a mammal in need of natural killer cell immune modulation. In another embodiment, the invention teaches administration of said therapeutic combination to a mammal infected with said SARS-CoV-2. In some embodiments dosage of said therapeutic combination is based on inflammatory and/or immunological parameters observed in patients with COVID-19.

Abstract: Disclosed are means, methods and compositions of matter useful for stimulation enhancement of T cell homing into tumors and overcoming tumor microenvironment. In one embodiment the invention provides an engineered T cell in which engagement of T cell receptor on said T cell results in upregulation of T cell attracting chemokines so as to induce an increased proportion of T cells to tumor cells. In another embodiment, T cell chemokine secreting cells are administrated intratumorally in order to augment T cell infiltration into said tumors. In other embodiments administration of lymphopoietic cytokines is performed intratumorally to enhance viability of T cells approaching and residing in the microenvironment. Combinations of agents which counteract tumor microenvironment induced immune suppression are also disclosed.

Abstract: Disclosed are aptamers designed to bind immunological checkpoint molecules while concurrently suppressing tumor associated gene expression through delivery of DNA molecules encoding short hairpin DNA. In one embodiment the invention provides an aptamer capable of binding PD-1 and/or PD-1 ligand while concurrently possessing ability to induce RNA interference to one more multiple other immune inhibitory and/or oncogenesis related genes. In one embodiment such a dual-targeting aptamer is utilized to induce systemic tumor abscopal effect.

Abstract: Disclosed are combination therapies for cancer utilizing the leverage of the adaptive immune system through chimeric antigen receptor (CAR) T cells, combined with leveraging the innate immune system by using CAR-macrophages (CAR-M) and CAR-natural killer (NK) cells. In some embodiments, the invention teaches the initial modification of the tumor microenvironment by administration of CAR-M and CAR-NK. The alteration of the tumor microenvironment results in reduction of barriers for CAR-T cells to enter the tumor, which allows for efficacy of CAR-T in treatment of solid tumors. In some embodiments adjuvant immunotherapies are utilized to expand immunological attack such as addition of complement, immunotherapeutic antibodies, chemotherapy and radiotherapy approaches.

Abstract: Disclosed are means, methods and compositions of matter useful for prevention of space flight associated bone density loss. In one embodiment, the invention provides cellular populations capable of suppressing osteoclast function and/or stimulating osteoblast activity. The use of mesenchymal stem cell populations alone, or more preferably, selected by expression of CD56 protein are disclosed. Cells may be administered systemically, or locally through the use of various matrices disclosed in this invention.

Abstract: Disclosed are prophylactic and therapeutic approaches to Orthopox viral infections. In one embodiment the invention teaches utilization of regenerative cell conditioned media as a prophylactic/therapeutic agent. Synergies with antivirals and immunotherapies are further described. In one specific embodiment, mesenchymal stem cells are activated in vitro with trigger agents activating Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) and conditioned media is isolated and utilized as a therapeutic. Quantification of activity is performed by assessment of antiviral activity and/or ability to stimulate NK mediated cytolysis. Additionally, means of treating Orthopox viral infections (Smallpox, Monkeypox, etc.) by direct administration of stem cells and/or products thereof such as exosomes are disclosed.

Abstract: Disclosed are means, methods and compositions of matter for prevention of hair loss and/or regeneration of hair follicles utilizing stem cell-based approaches and synergies with stimulating and/or hormone modulating agents. In one embodiment the invention discloses specific platelet rich plasma (PRP) combinations alone or with bone marrow stem cells to augment hair restoration and stimulate expansion of hair follicle associated T regulatory cell.