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Novel Treatment For Alzheimer’s Disease and Dementia

Pathological accumulation of phosphorylated Tau (pTau) and accumulation of amyloid-beta (Ab) fragments are the two major biochemical hallmarks of Alzheimer’s disease (AD). Effective strategies to remove Ab in AD-patient brains have been developed, but have not yet shown efficacy to slow cognitive decline in clinical trials. This finding has led to the idea that targeting Tau or combinatorial strategies that target both Tau and Ab are required to treat AD. Genetic, epidemiologic, and biochemical evidence suggests that predisposition to AD may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Stimulation of a brain specific cytochrome that converts cholesterol to 24-hydroxycholesterol, which in turn reduces cholesteryl ester. Reduction of cholesteryl ester has been demonstrated to reduce pathological Tau phosphorylation in human neurons made from induced pluripotent stem cells. Also, low dose Efavirenz/Sustiva reduces neurofibrillary tangles in a mouse model. The pathway may run from cholesteryl ester to Tau via the proteasome.

Use of UBA7 and its Regulated Genes as Novel Biomarkers in Treating Human Cancers

Human Ubiquitin-like modifier-activating enzyme 7 (UBA7) is a protein is involved in protein modification, specifically involving the pathway for protein ubiquitination. The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. UBA7  encodes a member of the E1 ubiquitin-activating enzyme family. Moreover, ubiquitination and ubiquitin-like post-translational modifications (PTMs) regulate activity and stability of oncoproteins and tumor suppressors. Biomarkers are very important as companion diagnostic tools to guide clinical practice in treating human cancers, especially for targeted therapies. In the era of precision medicine, it is important for development companion diagnostic tools that can guide clinical practice for treating human cancers using targeted therapies.

Novel microbial species that promote fetal tolerogenic immunity

New therapies to prevent the development of asthma and other chronic inflammatory diseases in infants using natural bacterial modulators of fetal immune development.

Neoantigen-specific antibodies for chemically directed immune targeting of KRAS tumors

UCSF scientists have discovered novel antibodies that can specifically and selectively recognize tumor-derived neoantigens. The antibodies can be used for IgG, BiTE or CAR-T-based targeted immunotherapy and small molecule-based directed immune targeting via combination therapy. This dual therapeutic approach has the potential to specifically recognize and treat KRAS (G12C) cancer cell populations with high specificity, significantly improve cancer treatment outcomes, and overcome risk of treatment resistance in patients.

Novel Methods To Eliminate Dormant Hiv Reservoirs

Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS) and AIDS-related disorders. There were 1.7 million new infections globally in 2018, and ~38 million people are currently living with HIV-1. Although the introduction of antiretroviral therapy (ART) has prevented millions of AIDS-related deaths worldwide, patients must continue to receive ART for the remainder of their lives. HIV-1 reservoirs persist even while subjects are on ART, leading to a rapid increase in viral replication when therapy is discontinued. Therefore, eradication of persistent HIV-1 reservoirs remains the main barrier to achieving a cure for HIV-1/AIDS.  The prevailing view of persistence suggests that the virus remains in a latent state in memory CD4+ T cells regardless of plasma viral loads, allowing the virus to establish a life-long infection in the host. Since the latent virus is refractory to existing antiretroviral therapies, curative strategies are now focusing on agents that reactivate viral replication and render it susceptible to conventional therapy. Any strategy aimed at controlling and eradicating viral reservoirs in HIV-1-infected individuals must target such latent reservoirs. The mammalian genome encodes thousands of long noncoding RNAs (lncRNAs, >200 nucleotides), including intergenic lncRNAs (lincRNAs), which are increasingly recognized to play major roles in gene regulation. The pathophysiological functions and mechanisms of lncRNAs in gene regulation have started to emerge. Work over the last few years has begun to uncover the role of lncRNAs in modulating HIV-1 gene expression.

Switchable Chimeric Antigen Receptor-Engineered Human Natural Killer Cells

The existing CAR-engineered T cell-based (CAR-T) therapy represents one of the most successful immunotherapy approaches developed in recent years. Most CAR-T cell therapy has been used clinically to treat hematological malignancies by targeting the B cell-specific antigen, CD19. However, this approach is not without limitations due to toxicities such as by neurotoxicity or cytokine release syndrome. Additionally, CAR-T cells function only as autologous cells due to graft-versus-host disease that would develop if cells were obtained from another person. Therefore, CAR-T cells must be produced on a patient-specific basis. NK cells, on the other hand, function as allogenic cytotoxic effector cells that do not have to be utilized on a patient-specific basis and are proven to be less toxic since they do not cause cytokine release syndrome, neurotoxicity, or graft-versus-host disease. For these reasons, CAR-engineered NK (CAR-NK) cells have increasingly attracted interest as an alternative CAR-cell therapy. However, there exist other unmet challenges. Targeting CAR-based therapies against solid tumors has been challenging due to the lack of truly tumor-specific antigens as most targets are shared by non-malignant cells and can cause toxicity due to “on-target, off-tumor” effects.” A fine-tunable CAR therapy is useful to better identify and target tumors while limiting this toxicity.

Triazolo/Phenylpyrimidine Compounds as Novel Candidate Treatments for Schistosomiasis

Schistosomiasis is a disease caused by infection with parasitic flatworms called schistosomes. The three major medically important species are Schistosoma mansoni (causing intestinal schistosomiasis in Africa and South America), S. japonicum (intestinal schistosomiasis in East Asia), and S. haematobium (causing genitourinary schistosomiasis in Africa and the Middle East). Signs and symptoms may include abdominal pain, diarrhea, bloody stool, or blood in the urine.  The treatment of schistosomiasis serves three purposes: reversing acute or early chronic disease, preventing complications associated with chronic infection, and preventing neuroschistosomiasis. The goal of treatment is to remove the worms that produce the eggs which, in turn, are responsible for disease morbidity and mortality. There is no effective vaccine against schistosomiasis.

Novel small molecule drugs for the treatment of sleep disorders and depression

UCSF scientists have identified novel small molecules which are selective agonists and inverse agonists of the melatonin receptor types MT1 and MT2. The molecules have high in vitro and in vivo potency and potential to be utilized as a novel therapeutic for treating depression, jet lag, and sleep disorders.

Use of Thiazolidinediones for Treatment of Eosinophilic Esophagitis Pathologic Remodeling

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.

Biomimetic Conductive Hydrogels

UCLA researchers in the Department of Bioengineering have developed a novel electrically conductive scaffold system with a hyaluronic acid (HA)-based hydrogel for biomimetic research to treat spinal cord and other central nervous system (CNS) injuries.

Improvement To Retroviral Vectors Containing The Human Ubiquitin C Promoter

UCLA researchers in the Department of Molecular Biology have developed a lentiviral vector, “pCCLc-roUBC”, containing the cellular promoter from the human ubiquitin C gene (UBC), to improve transgene expression in retroviral vectors.

Heart Assist Device for Patients

Researchers at UCI have developed a cardiac assist device for patients with failing heart functions. The device contracts and expands the heart with the help of a pacemaker to help restore natural heart pace and blood flow. 

Improved Highly Potent Specific Human Kunitz Inhibitor of Fibrinolytic Enzyme Plasmin

UCLA researchers in the School of Medicine have developed mutant polypeptides of the tissue factor pathway inhibitor-2 (TFPI-2) Kunitz domain 1 (KD1), which can serve as potent inhibitors of fibrinolysis.

New Indications For ENPP1 Inhibitors, Part Two

UCLA researchers in the Department of Medicine have developed small molecule ENPP1 inhibitors and monoclonal antibodies for treating myocardial infarction and ocular calcification.

New Indications For ENPP1 Inhibitors

UCLA researchers in the Department of Medicine have developed small molecule ENPP1 inhibitors and monoclonal antibodies for treating myocardial infarction and ocular calcification.

Blocking Synaptogenesis For Chronic Pain Management

Gabapentin is used for treatment of seizures and hypersensitivity to pain. Researchers at UCI have employed low-dosage gabapentin immediately after injury to block the development of chronic pain.

Chemical Modulators of Nurr1

Long thought to be undruggable, Nurr1 is a nuclear receptor and transcription factor involved in the development, maintenance, and survival of midbrain dopaminergic neurons, which makes it an attractive target for developing therapeutics for such indications of Parkinson’s disease, multiple sclerosis, and schitzophrenia.

Antitumor Activity Of Sd-101 Alone Or In Combination With A-Pd-1 Therapy In Tumors Resistant To Anti-Pd-1

UCLA researchers in the Department of Medicine have developed a novel antitumor treatment that works alone or in combination with anit-PD-1 therapy to target interferon signaling-deficient tumors or tumors with alterations in the antigen presentation machinery, that are resistant to anti-PD-1 therapy.

Chimeric Kinase Inhibitors with Increased Activity

This invention describes newly generated kinase inhibitors that demonstrate enhanced and attenuated action over their parent kinase inhibitors. These molecules can be used alone but, when combined with novel blocking molecules, the action of these chimeric kinases can be targeted for action in the central nervous system (CNS).

Technologies that can be Used to Selectively Bind Messenger RNA and Enhance Protein Translation

Control of gene expression is a general approach to treat diseases where there is too much or too little of a gene product. However, while there are many methods which are available to downregulate the expression of messenger RNA transcripts, very few strategies can upregulate the endogenous gene product. The vast majority of gene regulatory drugs which are commercially available or being developed are designed to knockdown gene expression (i.e. siRNAs, miRNAs, anti-sense, etc.). There exist some methods to enhance gene expression, such as the delivery of messenger RNAs; although, therapeutic delivery of such large and charged RNA molecules is technically challenging, inefficient, and may not be practical. There are also classical gene therapy approaches where a gene product is delivered as viral-encoded products (AAV or lentivirus-packaged). However, these methods suffer from not being able to accurately reproduce the correct alternatively spliced isoforms in the right ratios in cells.  

Anti-Obesity Target

The global epidemic of type 2 diabetes is increasing at an alarming rate in both Westernized and developing countries. In the United States alone, it is estimated that there are at least 30 million people with this disease. Metabolic syndrome is 2 to 3 times more prevalent than type 2 diabetes and is usually the precursor state for this disease, indicating that this type 2 diabetes epidemic will not abate in the near future. Insulin resistance is a key etiologic feature of the metabolic syndrome and type 2 diabetes, and obesity is far and away the most common cause of insulin resistance in humans. There is a well-known parallel global epidemic of obesity, and the great majority of type 2 diabetic patients are obese. Therefore, it seems logical to conclude that the obesity epidemic is the underlying driver of the type 2 diabetes epidemic. Unfortunately, at the present time there are a limited number of therapeutics available as way of preventing or treating obesity.

NOVEL ANTIBODIES AGAINST EPHA2 FOR RESEARCH, DIAGNOSIS, AND TREATMENT OF CANCER

A novel monoclonal human antibody specific to the cell-surface exposed protein EphA2, which is over-expressed in many forms of cancer and is a validated therapeutic target.

New Treatment For Aortic Aneurysms

Aortic aneurysms account for 1-2% of deaths in Western countries, and despite improvements in surgical repair, morbidity and mortality remain high, especially with thoracic aortic aneurysms and dissections (TAAD). Degeneration of the medial layer of the aorta leads to aortic dilation and/or rupture; pathological changes in the media include progressive elastin fiber fragmentation, loss of smooth muscle cells, and proteoglycan accumulation. Mutations causing hereditary TAAD affect proteins regulating transforming growth factor-β signaling (e.g., Loeys-Dietz syndrome and Marfan syndrome), or components of the smooth muscle cell contractile apparatus. Aortic pathology has been attributed to smooth muscle cell phenotypic alterations and activation of stress pathways, leading to increased production of tissue-destructive matrix metalloproteinases and increased oxidative stress. Abdominal aortic aneurysms (AAAs) may share with TAAD some of these pathogenic mechanisms. While blood pressure control with β-adrenergic or angiotensin receptor blockers modestly improve the prognosis of patients with TAAD, there is no treatment to prevent the pathologic changes in the aorta.          

Development of a Method to Treat Alzheimer’s Disease by Protection of Synapses

NMDA receptors (NMDARs) are principal regulators of synaptic signaling in the brain. Modulation of NMDARs’ function and trafficking is important for the regulation of synaptic transmission and several forms of synaptic plasticity. Postsynaptic density protein 95 (PSD-95) acts as a scaffolding protein and stabilizes the surface and synaptic expression of NMDARs. NMDA receptors (NMDARs) are ionotropic glutamate receptors that are expressed throughout the nervous system and play crucial roles in neuronal development, synaptic plasticity, learning and memory. PSD-95 (Post Synaptic Density protein) or SAP90, a membrane-associated guanylate kinase (MAGUK), is the major scaffolding protein in the excitatory postsynaptic density (PSD) and a potent regulator of synaptic strength. It is almost exclusively located in the post synaptic density of neurons and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels. Postsynaptic loss does not precede obvious Aβ (beta-amyloid or amyloid beta) and Tau deposition, but instead appears to occur as Aβ and Tau pathologies advance. This indicates that PSD-95 is an excellent intrinsic biomarker for post synaptic mechanisms and its expression is reduced in brain tissue from patients with Alzheimer’s Disease (AD) as well as in mouse models of AD.

Using Bacteria for Gut Health Improvement and Weight Management

Researchers at the University of California, Davis have developed a method of using bacteriocin peptides to reduce gut inflammation, improve gut barrier function, and reduce obesity in humans.

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