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Development of Novel Beta-Adrenergic Receptor Allosteric Modulators

The G protein-coupled receptors (GPCRs) are a very important family of cell surface receptors that respond to extracellular signals which then transduce those signals into intracellular responses.  They are also the largest family of targets of currently available therapeutics. Adrenergic receptors belong to the GPCR superfamily and their natural ligands are the catecholamines, epinephrine and norepinephrine. Adrenergic receptors can be further divided into two receptor subfamilies, α and β that exhibit differences in tissue distribution, ligand specificity and cellular output. The β adrenergic receptors (βARs) are important mediators in diseases like asthma, Parkinson’s disease, hypertension and heart failure. Therefore, there is a direct need for new modulators for the βARs receptors.

Development of a Potential Therapeutic for the Treatment of Alcoholism

Alcohol consumption is a major public health concern in the United States and according to the National Institute on Alcohol Abuse and Alcoholism, it is estimated that over 88, 424 people die on average for the years 2006-2010. Aside from death, excess alcohol consumption is linked with a host of other health-related problems, including Alcoholic Liver Disease (ALD) or alcohol-induced brain injury and alcohol-induced neuronal death, cirrhosis and astrogliosis. Therefore, there is an urgent need for a therapeutic which could potentially reduce addiction to alcohol. 

The Therapeutic Use of Human Oligosaccharides to Treat Atherosclerosis and/or Hyperlipidemia

In the United States and most other developed countries, atherosclerosis is the leading cause of illness and death. In 2015, cardiovascular disease, primarily coronary artery disease (atherosclerosis that affects the arteries supplying blood to the heart) and stroke, caused almost 15 million deaths worldwide, making atherosclerosis the leading cause of death worldwide. Atherosclerosis means hardening of the arteries due to the presence of plaques, which are deposits of fatty materials. Atherosclerosis can affect the medium-sized and large arteries of the brain, heart, kidneys, other vital organs, and legs. Atherosclerosis begins when an injured artery wall creates chemical signals that cause certain types of white blood cells (monocytes and T cells) to attach to the wall of the artery. These cells move into the wall of the artery. There they are transformed into foam cells, which collect cholesterol and other fatty materials and trigger growth of smooth muscle cells in the artery wall. In time, these fat-laden foam cells accumulate. They form patchy deposits (atheromas, also called plaques) covered with a fibrous cap in the lining of the artery wall. With time, calcium accumulates in the plaques. Plaques may be scattered throughout medium-sized and large arteries, but they usually start where the arteries branch. Existing treatment options for atherosclerosis and cardiovascular disease are aimed at lowering Low-density lipoprotein (LDL) cholesterol by either increasing hepatic LDLR expression by using statins and PCSK9 inhibitors, or by reducing cholesterol absorption by using ezetimibe. Further development of therapeutic strategies is warranted due to various drawbacks and limitations using the current therapeutic options.

Gene Editing of Monogenic Disorders in Human Hematopoietic Stem Cells

Researchers at the UCLA Department of Microbiology, Immunology & Molecular Genetics have developed novel methods to achieve efficient, precise gene integration and effective expression of cDNA cassettes to express normal versions of genes in hematopoietic stem cells.

Development of a Novel cAMP–Inhibitor that Restores Epithelial and/or Endothelial Barrier Integrity in Human Cells Infected by Pathogenic Bacteria

Pathogenic bacteria have evolved elaborate and clever ways to enter our cells and breach the protection offered by our innate immune system. To initiate disease, many bacterial toxins target a specific cell, usually by binding to a receptor and thereby gaining access to the cytoplasm to promote pathogenesis. Interestingly, a set of toxins produced by diverse bacterial species act by distinct mechanisms to dramatically increase the intracellular concentration of cAMP. This striking evolutionary convergence suggests that overproduction of this second messenger represents a successful strategy to promote growth and dissemination of infectious agents, as well as disease symptoms. The organisms that produce these toxins that disrupt cAMP include:  Bacillus anthracis (B.a. and Anthrax edema toxin- ET, LT), Bordetella pertussis (CyaA), and Vibrio cholerae (Ctx) will be the focus of this study.     Current therapies to alleviate symptoms of cholea and anthrax are less than adequate and demonstrate that there is an urgent need for updated strategies and therapies for the treatment of these pathogenic diseases.

Cirmtuzumab Targets ROR1+ Breast Cancer Stem Cells That Are Selectively Resistant To Cancer Chemotherapy

Advances in chemotherapy and endocrine therapy have reduced breast cancer mortality, but 20% of patients still relapse and ultimately succumb to this disease. One model accounting for this position is that there exists cancer stem cells (CSCs), which are relatively resistant to chemotherapy, have self-renewal capacity, can repopulate the tumor, and can spread to distant sites. If so, therapies that also target CSCs may improve treatment outcomes and patient survival. Studies have identified characteristics that distinguish CSCs from other cancer cells. Breast CSCs have phenotypic features that distinguish them from other neoplastic cells. For example the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in many cancers, but not by normal post-partum tissues.  Breast cancers with high-levels of ROR1 cells tend to be poorly differentiated and to express markers associated with epithelial-to-mesenchymal transition (EMT). In line with a role for ROR1 in tumor cell survival metastasis, high-level expression of ROR1 is associated with relatively short post-treatment disease-free or overall survival of patients with triple-negative breast cancer. However, the targeting of ROR1 in breast CSCs which constitute a subpopulation of cancer cells that are relatively resistant to conventional chemotherapy and have self-renewing capacities needs further investigation.

NOVEL TUMOR SELECTIVE INTERNALIZING ANTIBODIES

Novel human monoclonal antibodies recognize a cell surface antigen that has limited normal tissue expression but is highly overexpressed in several types of cancers, including mesothelioma, melanoma, head and neck cancer, lung cancer, glioblastoma multiforme, pancreatic cancer, ovarian cancer, breast cancer, prostate cancer, cervical cancer, skin cancer and testicular cancer. The antibodies can block tumor invasion, self-renewal and have potential to modulate immune effector cell function.

Probiotic for Inflammatory Bowel Disease

Prof. Declan McCole and his colleagues at the University of California, Riverside have identified segmented filamentous bacteria (SFB) as a symbiont that may be used to treat or prevent the relapse of UC.  Adherent invasive Escherichia coli (AIEC) are in higher abundance in IBD patients and significantly alter intestinal barrier function.  This altered intestinal barrier function may be measured by transepithelial electrical resistance (TER).  In cellular assays and tests on murine enteroids derived from the distal colon, the researchers showed that treatment of IBD with SFB reduced mouse AIEC  and protected against intestinal barrier dysfunction.  The TER measurements in SFB treated Caco-2 cells showed little change from TER of the controls.  Fig. 1 shows that Caco-2 cells cultured on transwells and pretreated with viable SFB (vSFB) protected against pathogenic mouse AIEC (mAIEC) and decreased TER which is a measurement of intestinal barrier function. The cells were also cultured with non-pathogenic K-12 E. coli as a control.  Fig. 2 shows Caco-2 bbe cells grown on transwells and pretreated with either viable SFB (vSFB) or heat-killed SFB (hkSFB). Caco-2 bbe cells treated with vSFB resisted adhesion of mAIEC.

Antibody Selection to Prevent or Treat Alzheimer’s Disease

Therapeutic antibodies have been developed to prevent or slow the cognitive decline in Alzheimer’s disease (AD) but with limited clinical success to date. These treatment failures suggest that antibodies vary in their therapeutic efficacy and that more effective antibodies or combinations of antibodies need to be identified. To address this issue, researchers at UCI have developed a novel screening platform that can identify antibodies that may prevent or treat AD or other neurodegenerative disorders with high efficacy from human blood.

In vivo optical biopsy applicator of the vaginal wall for treatment planning, monitoring, and imaging guided therapy

Pelvic floor disorders (PFDs) afflict nearly 25% of all women and carry a host of symptoms that can drastically reduce quality of life. Despite their prevalence, the complex and varied nature of such PFDs make them difficult to diagnose and treat. Researchers at UCI have developed an entirely integrated system that, for the first time, provides real-time monitoring of the vaginal wall tissue during diagnosis and treatment, allowing for more thorough diagnoses and more effective treatment methods.

New Platform and Methods for Generating Safe Cell Therapeutics

While some cell therapies have experienced success, many current cell therapies fall short in that enough cells do not reach the target tissue and/or the cells are incapable of producing clinically relevant thresholds of desired products sufficient to impact the disease state. Consequently, there is a major fundamental need to genetically engineer therapeutic cells to be more effective and robust using integrating viruses and powerful gene editing technologies like CRISPR, which can target ten to hundreds of genes simultaneously. However, this is highly problematic because the process of genetic engineering introduces dangerous unwanted mutations into the genome that can lead to cancer and other life-threatening diseases, especially if such cells permanently engraft into the body or fuse with host cells, which is common with stem cells. Therefore, the FDA does not readily permit the introduction of new genetic material or the extensive alteration of endogenous genes in cell-based therapies with the exception of CAR-T cells. For this reason, there is a major underlying need in the cell therapy sector to genetically enhance therapeutic cells to express gene products encoding biologics and then render them safe prior to clinical use. 

In Utero Prevention Of Congenital Heart Disease By Metabolic Intervention

UCLA researchers in the Department of Molecular Cell and Developmental Biology have discovered a method of preventing congenital heart disease through in utero treatment.

Identification of Novel Biomarkers to Detect Chronic Myelogenous Leukemia (CML) Progression

Generally, our current knowledge about cancer is based upon the mutations in protein coding genes, such as tumor suppressors and oncogenes. Recently, with advancements in the deep sequencing arena, focus has turned to the importance of epigenetic and post-transcriptional events in cancer progression and resistance associated with therapeutic treatments. These findings have revealed the complexity of gene expression at the RNA level. To that end, two of the most common RNA modifications are the editing of N6-methyl adenosines (m6A) and adenosine-to-inosine (A-to-I). For A-I conversion, Adenosine Deaminases Act on RNA (ADARs) enzymes targeting non-coding sequences and alterations in ADAR expression or activity can lead to cancer, but the pathogenic mechanisms remain under investigation.  Furthermore, malignant RNA editing, driven by ADAR1 activation has been shown to be a major contributor to cancer relapse and progression.

NOVEL GUT MICROBIOME-BASED DIAGNOSTIC FOR IDENTIFICATION OF NEONATES AT RISK OF CHILDHOOD ATOPY AND ASTHMA

UCSF researchers have developed a novel gut microbiome-based diagnostic test for early-life identification of atopy or asthma risk in children.

Approach For Efficient Protein Incorporation Into Recombinant Vaults

UCLA researchers in the departments of Medicine, Microbiology, Immunology & Molecular Genetics, and Bioengineering have developed a novel method for loading protein payloads into vault nanoparticle carriers.

Bioavailable Dual sEH/PDE4 Inhibitor for Inflammatory Pain

Researchers at the University of California, Davis, have developed a dual soluble epoxide hydrolase (sEH)/ phosphodiesterase 4 (PDE4) inhibitor for the treatment of inflammatory pain.

Small Molecule sEH Inhibitors to Treat Alpha-Synuclein Neurodegenerative Disorders

Researchers at the University of California, Davis have developed small molecule inhibitors to prevent or reverse the progression of neurodegenerative diseases or symptoms.

PTUPB Compound Potentiates Cisplatin-Based-First Line Therapies with No Additional Toxicity

Researchers at the University of California, Davis have discovered a compound that inhibits both cyclooxygenase-2 (COX-2) /soluble epoxide hydrolase (sEH) to improve effectiveness of chemotherapy while protecting normal tissue from cisplatin toxicity.

Development of Novel Inhibitors of New Delhi Metallo-beta-lactamase-1 (NDM-1)

Antibiotic-resistance in pathogenic bacteria has become a critical public health threat. A major mechanism of antibiotic resistance is microbial degradation of drugs by enzymes such as β-lactamases which degrade the β-lactam ring of β-lactam antibiotics, namely penicillins, cephalosporins, carbapenems and monobactams, inactivating them. There are four different molecular classes of β-lactamases (A-D). Three classes of β-lactamases (A, C, and D) utilize an active-site serine in covalent mechanisms that can be targeted by β-lactamase inhibitors coformulated with β-lactam drugs. In contrast, class B consists of metallo-β- lactamases (MBLs) that utilize one or two active site Zn(II) ion(s) to catalyze the hydrolysis of the β-lactam ring. The emergence of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1) and its variants, worldwide, has raised a major public health concern. NDM-1 hydrolyzes a wide range of β-lactam antibiotics, imipenem, meropenem, ertapenem, gentamicin, amikacin, tobramycin, and ciprofloxacin including carbapenems, which are the last resort of antibiotics for the treatment of infections caused by multidrug-resistant bacteria such as carbanenem-resistant Enterobacteriacae and Klebsiella pneumoniae. Currently, there are Inhibitors of NDM-1, both of which have liabilities, either due to adverse effects in mammals or off-target inhibitory activity. Therefore, a new type of NDM-1 inhibitor is needed.

A Novel Target for the Neutralization of Cancer Stem Cells in Glioblastoma

Researchers at UC Irvine have recently discovered a novel mechanism that can be exploited to disrupt the maintenance and self-renewal capacity of cancer stem cells. This finding has therapeutic implications for the treatment of Glioblastoma Multiforme (GBM), which is the most common, aggressive and lethal primary brain tumor.

Potent TMEM16A Small Molecule Treatment for Inflammatory and Reactive Airway Diseases, Asthma, Hypertension, Pain and Cancer

A novel class of 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as potent TMEM16A inhibitors

Selective Voltage Gated KV1.3 Potassium Channel Inhibitors

Researchers at the University of California, Davis, have discovered a composition of 5-phenoxyalkoxypsoralens that inhibits potassium channels to treat autoimmune diseases and disorders that involve abnormal homeostasis, body weight and peripheral insulin sensitivity.

Antisense Oligonucleotide Therapy for B Cell Mediated Cancers

Researchers at the University of California, Davis have developed a targeted therapy using an antisense oligonucleotide (ASO) to treat precursor B cell (pre-B) acute lymphoblastic leukemia (ALL).

The Use Of Parathyroid Gland Cells And Their Secreted Factors To Promote Islet Beta Cell Engraftments

This invention identifies a novel method to increases survival of transplanted islets in extra-hepatic sites (subcutaneous and intramuscular) through co-transplantation of pancreatic islet beta cells together with parathyroid glands (PTGs). This treatment can successfully be used for patients with type I diabetes.

Novel Therapy for Treating Fungal Infection of the Cornea

Fungal keratitis is an infection of the cornea caused by pathogenic fungi that is challenging to treat. This therapy is a novel topical application of a commercially-available malarial drug to treat fungal keratitis with fewer side effects than current treatments.

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