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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.

High Accuracy Machine Learning Model for Predicting Liver Cancer Risk

Researchers at the University of California, Davis have developed a method to predict if patients diagnosed with nonalcoholic fatty liver disease are at risk for developing liver cancer using a machine learning algorithm that analyzes a variety of easily available phenotypes and risk factors.

Humanized, potent monoclonal antibodies against murine and human integrin avb8 for cancer immunotherapy and prevention of corneal scarring after cataract surgery

Immunotherapy has revolutionized the treatment of many cancers, but even for the most sensitive tumor types most patients do not respond to current immunotherapy regimens. One major block to effective anti-tumor immunity is inhibition of the function of effector T cells by active TGFβ in tumors. For this reason, several major pharmaceutical companies have invested substantial resources in developing inhibitors of TGFβ ligands or TGFβ signaling to enhance anti-tumor immunity. However, because TGFβ isoforms (TGFβ1, 2 and 3) play multiple important homeostatic roles, highly effective inhibition of TGFβ function causes severe toxicity, as seen by the embryonic or perinatal lethality of knockout of each of the 3 mammalian TGFβs. Even the relatively ineffective TGFβ inhibitors that have entered clinical trials have been withdrawn because of unacceptable toxicity (cardiac valve thickening and skin cancer). We have thus spent the past 20 years developing drugs targeting TGFβ activating integrins, which only activate a small fraction of extracellular latent TGFβ in precise contexts relevant to specific diseases, with the goal of increasing precision and greatly reducing the potential for toxicity. 

Conjugates That Combine HDAC Inhibitors and Retinoids into Disease Preventatives/Treatments

Researchers at the University of California, Davis have developed methods for creating compositions with the potential to prevent or treat cancer or metabolic diseases. These compositions combine conjugates with covalently linked HDAC inhibitors and retinoids.

Sialic Acid Inhibitor in Cancer Treatment and Immunotherapy

Researchers at the University of California, Davis have developed a method of inhibiting sialic acid expression which is commonly related to bacterial and viral infections, metastatic cancer, and other pathogenic processes.

(SD2021-146) ANTICANCER AND ANTIFUNGAL SPLICE MODULATORS

While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation-driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators for the treatment of a broad array of malignancies characterized by splicing deregulation.  However, the inability to practically access gram-scale lead molecules with viable pharmacological properties continues to hinder their application.

(SD2020-497) Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

Blood Based T Cell Biomarker For Cancer Diagnosis And Treatment

In cancer care, specific characteristics of T cells can be used to measure a patient’s response to immunotherapy. Using single-cell RNA-sequencing coupled with TCR sequencing, scientists at UCSF and Harvard detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in the blood. Their method reveals specific protein signatures (biomarkers) on the surface of T cells that can be therapeutically targeted to treat melanoma and other forms of cancer. It presents a very attractive alternative to obtaining invasive biopsy samples from the tumor, and can be done much more quickly.  

Optimized Virus-like Particles for Cas9 RNPs & Transgene/HDR Template Delivery

The inventors have developed optimized methods for using virus-like particles for the co-delivery of Cas9 ribonucleoprotein complexes and: a lentiviral genome that encodes a large transgene, such as a chimeric angtigen receptor (CAR) transgene a lentiviral genome that does not encode a sgRNA expression cassette a method for nucleofecting VLPs + homology directed repair (HDR) donor template together to enhance HDR in treated cells  

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.

Intranasal Delivery of Oligonucleotides for Neurodegenerative Diseases

Delivery of oligonucleotide therapy to the central nervous system remains challenging. Neurodegenerative diseases, such as Huntington’s disease and Spinal Muscular Atrophy, can require intrusive and regular treatments, therefore a non-invasive delivery system would be very beneficial to patients. UC Irvine researchers have proposed a new method of therapeutic delivery utilizing a SARS-CoV-2 pseudovirus. Delivered intranasally, this system has the ability to bypass the blood brain barrier, making it an exciting approach to decrease risk for patients and ease the treatment process.

Bioengineered Wnt5a Therapeutics For Advanced Cancers

Researchers at the University of California, Davis have developed RNA-based therapeutics to treat Wnt5A-expressing cancers, including treatment-resistant prostate cancer.

T cell Receptor cDNAs to Treat Gliomas

Brief description not available

Natural Killer Cells with Enhanced Activity (SD 2021-141)

NK cells possess a native ability to kill tumors and virally infected cells without prior antigen priming. Furthermore, NK cells can be administered to patients across HLA allotypes, unlike T cells which require HLA matching to avoid graft-versus-host disease. Many trials utilizing adoptive transfer of allogeneic NK cells demonstrated complete remissions in patients with acute myelogenous leukemia (AML) who are refractory to standard chemotherapy. Another recent clinical study demonstrated effective treatment of lymphoid malignancies using allogeneic CAR-expressing NK cells, with minimal side effects. Thus, NK cells possess a number of advantages over T cells that enables them to be used as safe, effective, “off-the-shelf” adoptive cell therapy product to treat diverse malignancies. Antibody-dependent cellular cytotoxicity (ADCC) is a key pathway that mediates natural killer (NK) cell cytotoxicity against antibody-opsonized target cells. This process helps mediate the therapeutic efficacy of anti-tumor antibodies. On NK cells, ADCC occurs via engagement of antibody-coated target cells with activating receptor leading to proinflammatory cytokine upregulation, degranulation, and target cell death. Upon cellular activation, the     is cleaved from the NK cell surface. Cleavage of the ectodomain prevents further antibody binding and signaling, which dampens NK cell activity. Blocking activation-induced cleavage has been previously demonstrated to augment ADCC activity and provides a novel strategy to improve efficacy of therapeutic antibodies in combination with adoptive transfer of engineered NK cells. 

T Cell Receptor cDNAs to Treat Gliomas

Brief description not available

Broad spectrum anti-cancer agents

One of the main problems in using immune checkpoint inhibitors (e.g. PD-L1/PD-1/PD-L2/CTLA4) as a cancer treatment is that there is a large percentage of patients (~60-70%) who do not respond to the treatment or become resistant to it. Researchers all over the world are looking for ways to increase response to immunotherapy in this large population of patients, such as identifying new signaling pathways and/or new targets involved in this process as well as identifying synthetic molecules that can modulate the functions of those pathways and targets.

Deep Learning Techniques For In Vivo Elasticity Imaging

Imaging the material property distribution of solids has a broad range of applications in materials science, biomechanical engineering, and clinical diagnosis. For example, as various diseases progress, the elasticity of human cells, tissues, and organs can change significantly. If these changes in elasticity can be measured accurately over time, early detection and diagnosis of different disease states can be achieved. Elasticity imaging is an emerging method to qualitatively image the elasticity distribution of an inhomogeneous body. A long-standing goal of this imaging is to provide alternative methods of clinical palpation (e.g. manual breast examination) for reliable tumor diagnosis. The displacement distribution of a body under externally applied forces (or displacements) can be acquired by a variety of imaging techniques such as ultrasound, magnetic resonance, and digital image correlation. A strain distribution, determined by the gradient of a displacement distribution, can be computed (or approximated) from measured displacements. If the strain and stress distributions of a body are both known, the elasticity distribution can be computed using the constitutive elasticity equations. However, there is currently no technique that can measure the stress distribution of a body in vivo. Therefore, in elastography, the stress distribution of a body is commonly assumed to be uniform and a measured strain distribution can be interpreted as a relative elasticity distribution. This approach has the advantage of being easy to implement. The uniform stress assumption in this approach, however, is inaccurate for an inhomogeneous body. The stress field of a body can be distorted significantly near a hole, inclusion, or wherever the elasticity varies. Though strain-based elastography has been deployed on many commercial ultrasound diagnostic-imaging devices, the elasticity distribution predicted based on this method is prone to inaccuracies.To address these inaccuracies, researchers at UC Berkeley have developed a de novo imaging method to learn the elasticity of solids from measured strains. Our approach involves using deep neural networks supervised by the theory of elasticity and does not require labeled data for the training process. Results show that the Berkeley method can learn the hidden elasticity of solids accurately and is robust when it comes to noisy and missing measurements.

Lys-Covalent Pan-Inhibitors of Apoptosis Proteins (IAP) as Innovative Cancer Therapeutics

Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside (UCR) have developed novel Lys-covalent IAP inhibitors (Fig. 1) with low nanomolar activity and favorable PK (Fig. 2). When compared to Debio1143 (aka AT-406) and LCL 161, the UCR compounds have improved activity being irreversible.  Recently, new irreversible therapeutics in oncology have been developed as potential therapies for a variety of cancer. These irreversible agents present improved pharmacodynamics/ pharmacokinetics (PD/PK) properties over reversible agents, but their design is limited to targets that present a Cys residue within their binding site. UCR deployed a technology consisting of introducing a stable aryl-fluorosulfate electrophile that selectively interacts with Lys residues. UCR Compound 1 (Fig 1) is a potent, pan-IAP, Lys-covalent agent with favorable cell permeability and PK properties and that is likely superior to Debio1143 and LCL161 (Fig. 3). Fig. 1 Chemical composition and covalent docking of compound 1 in the binding pocket of the BIR3 domain of XIAP. Fig. 2 PK studies in mice with compound 1. Fig. 3 TNF sensitization of resistant melanoma cells by AT-406 (aka Debio 1143), LCL161 and the UCR compounds.  

Method And Device For Patterning Cells At Defined Interface

The present invention features a method and device that addresses the need for a low-cost and easy-to-use method and device to pattern a sharp interface between two or more cell populations or, more generally, two or more coatings wherein their interfacing properties are of interest. As a result, the present invention enables new types of experiments that analyze cell-cell interactions and the study of tissue biology in general. 

Potent and Effective Anti-Metastatic EphA2 Agonists

Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside have developed peptide-based EphA2 agonistic agents that have nanomolar activities. These agents, having the same mechanism of action as the natural (ephrinA1-Fc) ligands, effectively degrade EphA2 receptors and  delay cell migration in key cancer cell lines.  These agonistic agents may be effective therapeutics that may result in less unwanted side effects that have been observed in the clinic with ADCs targeting EphA2. Fig. 1 Top, X-ray structure of EphA2 in complex with UCR agent.. Bottom, Treatment with ephrinA1-Fc or UCR agent 135H12 on an orthotopic mouse model of prostate cancer with PC-3-GFP cells (n = 5 mice per treatment group). The mean fluorescence intensity related to metastases detected at day 7 from mice in each group, control (the solvent formulation used for 135H12), ephrinA1-Fc treated, 135H12 treated. Error bars represent standard deviation. ** p < 0.01.

3D-Bioprinted All-Inclusive Bioanalytical Platforms for Cell Studies

Common drug screen models, such as animals and 2D cell cultures, do not properly recapitulate human organ structure and environment. Using 3D bioprinting technology, researchers at UCI have developed all-inclusive customized organ-on-a-chip-like platforms. These platforms produce cell models that properly mimic the microenvironment of cells for drug screening and cell-therapeutic response studies.

Mitochondrial Transplantation to alter energy metabolism

Mitochondrial cardiomyopathy occurs when cardiomyocytes possess defective mitochondrial DNA. There is no cure and current treatment involves providing patients various dietary supplements. A novel biotherapy in which healthy mitochondria are transplanted directly into cells can help pave the way for treating mitochondrial-related diseases.

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