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COMPOUNDS FOR MODULATING EPITHELIAL 15-(S)-LIPOXYGENASE-2 AND METHODS OF USE FOR SAME

Lipoxygenases (LOX) are enzymes that catalyze the peroxidation of certain fatty acids. The cell membrane is mostly made of lipids (which include fatty acids), and peroxidation can cause damage to the cell membrane. The human genome contains six functional LOX genes that encode for six LOX enzyme variants, or isozymes. The role that each LOX isozyme plays in health and disease varies greatly, spanning issues such as asthma, diabetes, and stroke. LOX enzymes are extremely difficult to target due to high hydrophobicity. Potential leads are often ineffective because they are either not readily soluble or not selective for a particular LOX enzyme.  Studies have implicated human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) in various diseases. h15-LOX-2 is highly expressed in atherosclerotic plaques and is linked to the progression of macrophages to foam cells, which are present in atherosclerotic plaques. h15-LOX-2 mRNA levels are also highly elevated in human macrophages isolated from carotid atherosclerotic lesions in symptomatic patients. Children with cystic fibrosis had reduced levels of h15-LOX-2, which affects the lipoxin A4 to leukotriene B4 ratio. Furthermore, the interactions of h15-LOX-2 and PEBP1 changes the substrate specificity of h15-LOX-2 from free polyunsaturated fatty acids (PUFA) to PUFA-phosphatidylethanolamines (PE), leading to the generation of hydroperoxyeicosatetraenoic acid (HpETE) esterified into PE (HpETE-PE). Accumulation of these hydroperoxyl membrane phospholipids has been shown to cause ferroptotic cell death, which implicates h15-LOX-2 in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.  

Novel molecular target and approach(es) for the bidirectional modulation of T-cell function

Researchers at UC Irvine have identified and tested a molecular target that regulates T cell function during chronic viral infection and cancer. The molecular target is one of the high mobility group proteins (HMGB2). HMGB2 is a DNA binding protein that regulates transcriptional processes, meaning that its modulation will have profound effects on T cell differentiation and ultimate function by altering the expression of many genes.

Gene Targets For Manipulating T Cell Behavior

Brief description not available

(SD2020-447) An anti-inflammatory peptide

UC San Diego researchers synthesized a cell‐penetrating NEMOActPep where the NEMO peptide was fused to a peptide known to penetrate cell membrane. They also synthesized the corresponding mutant version where all six critical amino acids within this NEMOActPep were mutated to glycines.Currently, UC San Diego is looking for a company interested in developing US Patent Rights.

Methods and Compositions for Treating Inflammatory Diseases

Immune responses are crucial in fighting against infections. An uncontrolled immune response, however, can be deadly. Sepsis is one such inflammatory disease that can lead to organ failure and death, so it is crucial to develop new sepsis therapies. Long noncoding RNAs (lncRNAs), although not translated into proteins themselves, can regulate gene expression in biological processes. Studies have shown that lncRNAs can regulate immune responses, which leads to substantial interest in implicating lncRNAs in inflammatory diseases.

Novel Cell Therapy for CTLA4 Haploinsufficiency

Scientists have developed a CRISPR-Cas9 based genome editing method for universal correction of disease-causing mutations in the CTLA4 gene, which most commonly manifest as a Primary Immunodeficiency. Current treatment involves monthly IV injections or weekly subcutaneous injections of a recombinant CTLA4-Ig fusion protein abatacept. This invention includes one-time infusion of a CTLA4-corrected autologous T cell therapy. The corrected patient cells are generated by ex vivo electroporation of a specific gRNA:Cas9 ribonucleoprotien (RNP) complex and cognate homology-directed-repair template (HDRT) targeting a functional copy of the CTLA4 gene within an intronic region of the endogenous CTLA4 gene. This combination allows for (1) highly efficient knockin (up to 70% in patient cells), (2) cell-type and context specific regulation of CTLA4 expression under natural promoter and regulatory elements, and (3) preservation of endogenous CTLA4 expression in uncorrected cells.

Distinct Metabolic States Guide Maturation of Inflammatory and Tolerogenic Dendritic Cells

Scientists at UCSF and the Parker Institute of Cancer Immunotherapy have developed methods for characterizing dendritic cells as well as methods for identifying a dendritic cell as either an inflammatory or a tolerogenic dendritic cell. Their results provide important insights into previously obscured metabolic heterogeneity impacting immune profiles of immunogenic and tolerogenic dendritic cells (DC).

METHODS FOR PREDICTING THE RESPONSE TO METHOTREXATE AND TREATING RHEUMATOID ARTHRITIS

Researchers at UCSF have developed methods of treating Rheumatoid arthritis and for predicting the response of patients to methotrexate. 

AUTOANTIBODIES AS BIOMARKERS FOR AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1

Researchers at UCSF and the Chan Zuckerberg Biohub have identified multiple common autoantibody targets in APS1 patients through proteome-wide programmable phage-display.

Methods to Prevent and Treat Diffuse Large and Other B Cell Lymphomas

Professor Ameae Walker from the University of California, Riverside, Professor Srividya Swaminathan from the City of Hope Beckman Research Institute and their colleagues have developed a method for the prevention and treatment of B cell lymphomas. This technology works by systemically inhibiting expression of one form of the set of cell surface molecules that allow cells to respond to prolactin. This highly specific technology suppresses the deleterious downstream effects of prolactin that promote and sustain abnormal B cells. This invention is advantageous compared to existing technologies: all measures in mouse models and analysis of human cells suggest it is nontoxic and therefore will have significantly fewer, if any, side effects. It may also be used together with anti-psychotics that elevate prolactin. Finally, the technology includes a method for screening populations susceptible to development of DLBCL and other B lymphomas for early signs of disease. Antimaia Acts at Three Stages of B Lymphoma Development: 1) Antimaia, a splice modulating oligonucleotide (SMO) that decreases expression of the long form of the prolactin receptor, reduces the number of premalignant cells and the formation of abnormal antibody-producing cells. This also improves the symptomatology of autoimmune disease. 2) Antimaia prevents the conversion of premalignant to overt malignant B cells. 3) Antimaia kills B lymphoma cells. Antimaia works by reducing the number of long and intermediate form prolactin receptors (LF/IF PRLR) without effect on short receptors (SFPRLR). PRL, prolactin; Bcl2, B cell lymphoma 2; Myc, a proto-oncogene.

Leveraging microbiome bacteria, bacterial modulators, and novel microbial species for prevention, diagnosis, and treatment of inflammatory diseases, respiratory system infections, and premature birth

The following technologies encompass a portfolio of microbiome-centric inventions intended to address unmet diagnostic and treatment needs in the areas of inflammatory disease and respiratory system infections, including prevention in infants. 

Anti-Hla-A2 Chimeric Antigen Receptor

Brief description not available

Integrin Binding to P-Selectin as a Treatment for Cancer and Inflammation

Researchers at the University of California, Davis have developed a potential drug target for cancer and inflammation by studying the binding of integrins to P-selectin.

Modulating MD-2-Integrin Interaction for Sepsis Treatment

Researchers at the University of California, Davis have developed a potential therapeutic treatment for sepsis by modulating the interaction between integrins and Myeloid Differentiation factor 2 (MD-2).

Peptide Inhibitors of Human Voltage Gated Proton Channel hHv1 Activity to Reduce Inflammation

Human voltage-gated proton channels (hHv1) are implicated in a wide range of biological responses, including capacitation of sperm and stimulation of the innate immune response. Human sperm undergo a process called capacitation in the female reproductive tract, whereby intracellular pH rises and stimulates a progesterone-induced Ca2+ influx.  Researchers at the University of California, Irvine have discovered that this calcium influx is controlled by albumin activation of Hv1 voltage-gated proton channels.  Albumin activation of hHV1 in neutrophils also supports production and release of reactive oxygen species and protease during the immune respiratory burst.  These findings demonstrating a stimulatory role of albumin in both sperm and neutrophils has led to new therapeutic approaches to fertility and the treatment of inflammatory diseases.

Kaposi Sarcoma Associated Herpesvirus Gene Function and Methods for Developing Antivirals, Anti-KSHV Vaccines, and KSHV Based Vectors

The inventors present a novel strategy for achieving pathogen opportunistic pathogenesis, with broad implications for treating infectious diseases. In a comprehensive analysis of Kaposi sarcoma associated herpesvirus (KSHV), a medically important virus, the inventors discovered novel antiviral targets and gene function, and identified opportunistic factors with dual functions of regulating both the immune environment/responses and viral reactivation/replication. This discovery includes:A collection of KSHV mutants with inactivation or deletion of each of the 91 predicted open reading frames (91 mutant strains). Methods and reagents (e.g. primers) for construction of the collection of KSHV mutants. The identity of 44 KSHV essential genes, which represent potential antiviral targets (including 27 newly identified essential genes). Methods for construction of gene-inactivation and rescued mutants, and for tagging and introducing foreign genes into the KSHV genome. These approaches can be used for vector and vaccine development. Growth properties of viral mutants with inactivation of non-essential genes.Methods for screening mutants in different human cell lines.Opportunistic factors of KSHV and all other animal viruses that have dual functions as both the modulators of immune environment/response and regulators of viral reactivation/replication.   

Novel Estrogen Receptor ß (ERß) Drugs for the Treatment of Multiple Sclerosis (MS)

Prof. Seema K. Tiwari-Woodruff from the University of California, Riverside, Prof. John Katzellenbogen and colleagues from the University of Illinois have developed novel estrogen receptor β (ERβ) drugs for the treatment of MS. These novel MS drugs are specific for ERβ and have tremendous potential for the treatment of MS as well as other neurodegenerative diseases. In general, estrogens have anti-inflammatory and neuroprotective activities and clinically reduce the severity of MS and other neurodegenerative diseases. The compounds are more superior to other estrogenic drugs due to their specificity for ERβ and lack of undesirable effects such as feminization and increased risk of cancer. Fig 1: Therapeutic treatment with the UCR ERβ ligands began at peak disease (day 17) and was continued daily till day 36. ERβ ligands (blue, and orange) significantly attenuated clinical disease severity compared to vehicle treatment (red).  

Inhibitors of Bromodomain and Extra-Terminal (BET) Family Proteins as Potential Treatments for Drug-Resistant Tumors

Researchers at the University of California, Davis have developed small molecule inhibitors for use in treating drug-resistant tumors – including cancerous tumors.

Clearance of Senescent Cells by Activation of the Immune Response

Researchers at UCSF have developed a method to selectively clear senescent cells by stimulating an immune response. Accumulation of senescent cells underlies a number of disease conditions and age-related pathologies. Current approaches to clear this cell type use senolytics, these are small-molecules that induce cell death of the senescent cells. Unfortunately, these compounds are not truly specific and affect other non-pathogenic cells. UCSF researchers eliminate these off-target effects by utilizing the body’s immune system to selectively target senescent cells for clearance. They do this by activation and expansion of certain immune cells. Stimulating the immune system to clear these cells is unprecedented in the field and offers a new therapeutic modality to treat senescence associated conditions. The technology has been fully validated in a laboratory setting.

Modulation of Protein Tyrosine Phosphatase Receptor Type A (PTPRA) to Treat Arthritis

Fibroblast-like synoviocytes (FLS) in the intimal lining of the joint synovium control the composition of the synovial fluid and extracellular matrix (ECM) of the joint lining. In rheumatoid arthritis (RA), FLS become aggressive and invasive, contributing to many aspects of RA pathology. FLS produce matrix metalloproteinases (MMPs) that break down the ECM, directly invade and digest the articular cartilage, promote bone erosion, and promote inflammation through secretion of interleukin 6 (IL-6), chemokines, and other inflammatory mediators. FLS are highly sensitive to the inflammatory environment present in rheumatoid joints. Growth factors, especially platelet-derived growvth factor (PDGF), stimulate FLS invasiveness. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF) and interleukin-I (IL-1), enhance FLS aggressiveness, pro-inflammatory features and MMP production. Targeting of molecules that control FLS invasiveness and inflammatory output is being considered an option for development of new therapies for RA.   Many signaling pathways controlling FLS behavior rely upon phosphorylation of proteins on tyrosine residues, which results from the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). We found that a protein (PTPRA) belonging to a novel and currently untapped class of drug targets is present at high levels in cells lining the joints of RA patients, where we believe it promotes the aggressive behavior of these cells in joint inflammation and destruction.

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