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.

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.

Modeling diseases as networks has helped simplify an otherwise complex web of multi‐cellular processes; however, an exclusive reliance on symmetric relationships in these networks overlooks the existence of disease continuum states and loses information relevant to pathogenesis and for the development of therapeutics. Network‐based analyses severely influenced by symmetric analyses have helped formalize Network Medicine as a field and deliver many successes, but drugs that can predictably re‐set the network in complex multi‐component diseases are yet to emerge.

Regulatory T cells (Treg) play a critical role in controlling immune responses, chronic inflammation and autoimmune disease. Integrin activation in CD4+ FoxP3+ Treg is crucial to the maintenance of Treg numbers and function in vivo. Tregs also express high levels of the low affinity IL2 receptor CD25 (IL2Ra, TAC) on their cell surface. One mechanism by which Tregs are thought to limit immune responses is by sequestering the available IL2, effectively starving effectors and leading to peripheral tolerance. Previous work by the inventors showed that activation of integrin adhesion receptors were critical to the functioning and maintenance of peripheral Tregs. The present invention describes antibodies that specifically activate integrins on Tregs but not on conventional T cells. These antibodies promote the proliferation and outgrowth of Tregs but not of conventional T cells in vitro.   Thus, treatment with such antibodies would be expected to ameliorate auto-immunity.

Esophageal inflammatory disorders are gaining increased recognition in both adults and children. One example is eosinophilic esophagitis (EoE), which is an emerging and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as esophageal cellular changes such as basal zone hyperplasia and esophageal remodeling that includes fibrosis and smooth muscle dysfunction. These complications can lead to trouble swallowing, strictures,and food impactions. EoE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure. EoE diagnosis is often associated with other hypersensitivity disorders, including asthma, rhinitis, and other food and aeroallergen inhalant sensitivities. Diagnosis requires the finding of 15 or more eosinophils per high power field (eos/hpf) within esophageal mucosal biopsies. Although EoE is becoming more frequently diagnosed throughout developing countries, many aspects of the disease remain unclear including its etiology, natural history and optimal therapy. Symptoms of EoE often mimic those of gastroesophageal reflux disease (GERD) and include vomiting, dysphagia, pain and food impaction. In the absence of long-term treatment, up to 70-80% of adults with eosinophilic esophagitis (EoE) may go on to develop esophageal strictures. This disease now is likely to occur in 1 in 1000 people in the population and will have a dramatic effect on the patients’ quality of life. While there are therapies that control inflammation, not all patients respond to these therapies and continue to progress to fibrotic changes. There are currently no medical treatments to directly target esophageal fibrosis.

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection.

CAT2 is a membrane associated protein involved in the cellular uptake of cationic amino acids such as arginine, lysine and ornithine. CAT2 plays a regulatory role in the activation of macrophages. Arginine is a substrate for nitric oxide synthase (NOS) during the production of nitric oxide (NO). The release of NO by inflammatory cells contributes to the progression of diseases such as cancer, arthritis, inflammatory bowel disease, Crohn's disease, and atherosclerosis. CAT2 plays a role in controlling inflammation and IL-17 activation in an injury model of colitis.

Macrophages respond to pathogens and tissue damage via pattern recognition receptors (PRR) that sense pathogen (PAMP) or damage (DAMP) associated molecular patterns. NLRP3, a member of the Nod-like receptor (NLR) family that is induced upon macrophage activation, senses cytosolic oxidized mitochondrial DNA (ox-mtDNA) that is generated when activated macrophages are exposed to NLRP3- activating DAMPs, such as ATP, uric acid, or amyloid β, triggers IL-1β and IL-18 production and release. IL-1β and IL-18 are members of the IL-1 family of cytokines representing two of eleven members. As a whole, the IL-1 group of cytokines can induce strong inflammatory signals. Moreover, IL-1β and IL-18 are unique members because they are inactive until undergoing proteasomal cleavage by caspase-1 leading to the formation of active biological forms. Recent work has shown that NLRP3 inflammasome dependent production of IL-1β and IL-18 is involved in the pathogenesis of many devastating diseases, including cancer, Alzheimer’s disease, rheumatoid diseases and cryopyrin-associated periodic syndromes. and autoimmune diseases such as lupus or Still’s diseases. Thus, there exists a need to modulate the production of both IL-1β and IL-18.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and has been associated with poor quality of life and frequent complications requiring hospitalization and surgical procedures. Current therapies for IBD typically target neutralization of inflammatory cytokines, blockade of receptors, or inhibition of inflammatory cell functions. Despite current approaches, it is still difficult to control disease severity and maintain quality of life. One important phenotype of IBD that may offer an opportunity for gaining increased understanding of the disease is that up to 40% of individuals with inflammatory diseases of the colon have extra intestinal manifestations. Foremost in these extra intestinal symptoms are skin or oral disorders such as erythema nodosum, pyoderma gangreneosum and aphthous stomatitis. The presence of diseases associated with IBD at sites far from the gut support several hypotheses that IBD is a systemic disorder of circulating bone marrow derived immunocytes, a consequence of dysbiosis of the microbiome or a generalized disorder of epithelial function. Furthermore, appropriate function of the epithelial barrier is necessary to regulate the interactions between microbes and the host and maintain health.

A dynamic set of complex interactions between intestinal microbes, intestinal epithelial cells and intestinal immune cells are key in maintaining normal intestinal homeostasis as well as in the etiology of Inflammatory Bowel Disease (IBD). It is becoming clear that regulatory T cell-mediated control of inflammation is critical for the maintenance of immune tolerance in gut. Since 1970s, it has been suggested that CD8+ regulatory T cells play an important role in immune regulation of autoimmune diseases, transplant tolerance, and homeostasis of cellular and humoral immune responses. Among Treg subpopulations, an important role for Foxp3+CD4+ Treg and Foxp3- IL-10-secreting CD4+ T cells has been elucidated, while the function of CD8+ regulatory T cells in the gut has been hampered by an inability to distinguish them from conventional CD8+ T cells. Normally specific cytokines and transcription factors are the driving factors for maintaining the expression of a particular T cell phenotype.

Rheumatoid arthritis (RA) is a lifelong, systemic autoimmune disease that affects women three times more frequently than men, often in their most productive and childbearing years. Pregnancy in women with RA poses a therapeutic challenge. Some anti-rheumatic drugs can cross the placenta and harm the fetus and/or are transferred into breast milk and harm the breastfed baby. Teratogenic compounds like methotrexate and leflunamide are to be avoided and high dose steroids may be associated with a premature rupture of the membranes. The high risk of drug transfer into breast milk often leads to the recommendation for women to cease breastfeeding.  While the exact cause of RA remains to be elucidated, it is known that chronic macrophage inflammation plays a key role in the development and progression of rheumatoid arthritis. The ability to attenuate macrophage inflammation and suppress the secretion of pro-inflammatory cytokines, like interleukin (IL)-1beta and IL-6 would help in the treatment of RA.  

The NLRP3 inflammasome is a molecular machine that becomes activated during acute and chronic inflammation and leads to production of biologically active IL-1β and IL-18 that initiate inflammatory responses triggered by tissue damage. The NLRP3 inflammasome has also been implicated in many chronic inflammatory and degenerative diseases from gout, osteoarthritis, atherosclerosis to Alzheimer’s disease. Currently, there are no effective ways to inhibit the NLRP3 inflammasome, thus there is a therapeutic need for this class of molecule.

The gut is a complex environment; the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of trillions of microbes, diverse microbial products, food antigens and toxins to the largest immune system in the body. The gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium. Loosening of the junctions induced either by exogenous or endogenous stressors, compromises the gut barrier and allows microbes and antigens to leak through and encounter the host immune system, thereby generating inflammation and systemic endotoxemia. An impaired gut barrier (e.g. a leaky gut) is a major contributor to the initiation and/or progression of various chronic diseases including, but not limited to, metabolic endotoxemia, type II diabetes, fatty liver disease, obesity, atherosclerosis and inflammatory bowel diseases. Despite the growing acceptance of the importance of the gut barrier in diseases, knowledge of the underlying mechanism(s) that reinforce the barrier when faced with stressors is incomplete, and viable and practical strategies for pharmacologic modulation of the gut barrier remain unrealized.

Regulatory T cells (Treg) are important to control immune homeostasis and control inflammation. In autoimmunity Tregs play a critical role in down-sizing autoreactive T cells and, via interleukin-10 (IL-10) secretion, they regulate not only inflammation but also the fibrotic process that often complicates systemic autoimmune diseases. IVIG therapy is successfully used in many autoimmune conditions, such as immune-mediated thrombocytopenia, autoimmune hemolytic anemia, autoimmune vasculitides and in neurological conditions including Guillain-Barré syndrome, narcolepsy, Parkinson’s, Alzheimer’s.  The expansion of Fc-specific Treg may account as the critical mechanism as the autoimmune pathogenesis in these diseases is now proven and the immunodominant Fc peptides bind HLA molecules strongly associated with these diseases. IVIG treatment is very expensive and is provided as an infusion that requires hospitalization, so alternative treatments are needed. Immune regulation appears to be the most relevant therapeutic success in down-sizing endothelial inflammation and the vasculitis in Covid-19 infected patients. Suppressive lymphokines and in particular interleukin (IL)-10, the hallmark of regulatory T cells, regulates IL-1 and IL-6 secretion in the vascular compartment. Fc immune modulatory peptides are anticipated to stimulate Treg with potential effects not only on naïve T cell differentiation toward a pro-inflammatory phenotype, but also on innate cells representing a novel therapeutic approach with potential long lasting effects in maintaining  the immune homeostasis.

There are over 300 human-specific genes that are not represented in the genomes of animals used to model complex human disease.  The human-specific gene CHRFAM7A for example is expressed on leukocytes and epithelial cells and may gauge the inflammatory response in human cells.  The promoter controlling CHRFAM7A expression is differentially modulated by inflammation and thus may represent a therapeutic target to modulate the inflammatory response.  For example, because the neuroinflammatory response to infection, tissue repair and regeneration, is regulated by the α7-acetylcholine receptor (α7nAChR), the emergence of CHRFAM7A in humans may redefine how the human brain regulates the inflammation.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that mainly affects the synovial joints leading to chronic inflammation, joint destruction and loss of function. Pathogenesis of the disease involves a complex interaction between the innate and the adaptive arm of the immune system in concert with the resident synovial fibroblasts. These fibroblasts-like synoviocytes (FLS), which display an aggressive/transformed phenotype, contribute to synovial inflammation and cartilage damage by producing inflammatory mediators, recruiting and activating immune cells, and invading articular cartilage. Although treatment of RA has improved, a significant proportion of patients are partial responders with continued disease activity. Furthermore, the currently available disease modifying drugs do not directly target FLS. Thus, new rationally designed disease modifying agents are needed to replace or complement current therapies.

Rosacea is a chronic skin condition characterized by recurrent episodes of flushing, erythema, vasodilation, telangiectasia, edema, papules, pustules, hyperplasia, fibroplasia, itching, burning, pain, and skin tightness. Symptoms of rosacea are exacerbated by sun exposure, hot weather, immersion in hot water, high humidity, sweating, exercise, emotional stress, and spicy food. The skin condition usually begins between the ages of 30 to 50 and occurs more frequently in women than men. An estimated 16 million people are affected by rosacea inflammation in the United States. Oral and topical antibiotics are usually the first line of treatments prescribed for rosacea patients. However, they can cause serious side effects in some patients and do not address the underlying condition. Topical application of steroids may also help alleviate the symptoms, but it can also aggravate the condition. In addition, long term treatments can be inconvenient, lasting for as long as two years.

Bronchial asthma is a chronic and heterogeneous inflammatory disorder of the conducting airways with immune and non-immune etiologies. Although the underlying molecular basis of asthma is not completely understood, inflammation is a key pathological feature of bronchial asthma. The increasing prevalence in Western countries (approximately 15% of children and 8% of adults) supports the vast resources deployed to find treatments and drugs that act upon pathways not targeted in current therapies are of particular interest.

As part of a comprehensive campaign to screen for effective vaccine adjuvants, 180,000 compounds were tested in a cell-based HTS screen to assess ability to activate NF-kB. Several classes of scaffolds bearing appropriate substitutions were found to stimulate innate immune responses and some of these scaffolds were structurally different from all other known ligands. More interestingly, the structure of one class of scaffolds challenges current dogma regarding what is necessary for efficacy.

This invention provides microRNA therapeutics that augment blood vessel growth, which may have application for indications where it is desired to reduce or stimulate angiogenesis. Reducing or inhibiting angiogenesis may be useful for indications such as degenerative eye diseases and cancer. Stimulating blood vessel growth may be useful for treating indications such as cardiovascular, thrombotic or ischemic diseases. Cells lining blood vessels are usually among the least proliferative cell types, but this desired quiescence may be interrupted in response to growth factors during pathological neovascularization manifested in disease states such as macular degeneration and cancer. MicroRNAs are known to be key regulators of angiogenesis and specific miRNAs have been found to be effective toward these indications.

While inflammation is a beneficial component of the body’s response to harmful stimuli, prolonged or excessive inflammation triggers a wide variety of diseases. Current anti-inflammatory drugs (steroids, NSAIDs and immune selective anti-inflammatory derivatives) have undesirable side effects and for many indications including dermatology, drugs that act by a novel MOA may be more efficacious.

  It has been shown recently that in addition to their classical role in desensitizing G protein coupled receptors (GPCR’s), beta-arrestins can act as signaling molecules  independently and certain ligands (biased ligands)  can selectively activate one pathway but not the other .  Different biological responses have been observed with such beta-arrestin biased agonists, compared with traditional GPCR therapeutics designed to activate G-proteins.  However, the lack of well characterized ligands for the beta-arrestin pathway demonstrates there is a need   for effective screening methods to obtain selective  therapeutics  that could avoid  the side effects of mediating G-protein signaling.

The past two decades has resulted in a marked increase in our knowledge about phospholipase A2 (PLA2) enzymes. The PLA2 superfamily of enzymes has been divided into four main types: secreted sPLA2s, cytosolic cPLA2s, calcium-independent iPLA2s, and lipoprotein-associated/PAF acetyl hydrolase LpPLA2s.The association of the different types of PLA2s with diverse indications has justified pharma’s interest in developing selective inhibitors to the specific types. Undeveloped indications exist in the central nervous system (CNS) and the ability to target these underserved indications would enable a new means for targeting the underlying inflammatory causes of numerous diseases.

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