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Deep Learning-Based Approach to Accelerate T cell Receptor Design

Researchers at the University of California, Davis have developed a deep learning simulation model to predict mutated T-cell receptor affinity and avidity for immunotherapy applications.

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.

Positive Allosteric Modulators Target TRPV1 with Analgesic Effects

Researchers at the University of California, Davis have developed de novo positive allosteric modulators (PAMs) that bind to TRPV1 proteins involved with pain-sensing in order to provide analgesic effects.

(2020-266) Protein Domains For Modulation Of Rna Stability And/Or Translation

Existing art in modulation of gene expression by nucleic acid targeting mechanisms primarily comprises methods for REDUCING gene expression, e.g. via DNA targeting (CRISPR gene knockout, reduction of transcription via CRISPR-i), or RNA targeting (shRNAs/siRNAs, ASOs, microRNA mimics). ENHANCEMENT of gene expression on the RNA level has been achieved using microRNA inhibitors; however the effects are typically small and are not target-specific (many other microRNA target-RNAs are also upregulated).The molecular functions of the majority of RNA-binding proteins (RBPs) remain unclear, highlighting a major bottleneck to a full understanding of gene expression regulation. 

Novel Agonist alpha2aAR Analgesics

Brief description not available

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.

Laser Photocoagulation To Stabilize Collector Channels To Enhance Aqueous Flows

Inventors at the University of California, Irvine have developed a laser-emitting device that treats glaucoma by enlarging and stabilizing collector channels in order to enhance aqueous outflow and reduce intraocular pressure (IOP).

Acid Degradable Solid Lipid Nanoparticles

The inventors demonstrate that polyethylene glycol (PEG) conjugated to cholesterol via an acid degradable linkage composed of an azide-benzaldehyde acetal has the potential to allow solid lipid nanoparticles (SLNs) to be PEGylated with mole ratios up to 50%. The azide-benzaldehyde acetal, has its azide in the para position, and generates stable acetals with a t ½ of > 1000 minutes at pH 7.4. These PEG-acetals can be formulated into SLNs, and stored, and then reduced prior to biological use, to generate an amino acetal that has t ½ < 60 minutes at pH 7.4 and several minutes at pH 5.0. The ultra-PEGylated lipids were efficient at transfecting a variety of organs, including the muscle, the lung, spleen and liver and were also able to transfect the blood. Acid degradable PEG-lipids have great potential for overcoming the PEG dilemma, but have previously been challenging to develop due to the synthetic challenges associated with working with acetals and their instability at pH 7.4. (SLNs contain a PEGylated lipid, generally in the 1-5% range, which is needed to maintain SLN stability, size, and tissue diffusion, and lower toxicity. However, excessive PEGylation also results in lower cell uptake and endosomal disruption — a paradox referred to as the PEG dilemma.) The inventors anticipate numerous applications of the azide-benzaldehyde acetal linker, given its unique ability to be stable prior to reductive activation. 

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.

Multiplex Epigenetic Editing using a Split-dCas9 System

Researchers at the University of California, Davis have developed a new epigenetic editing system that overcomes packaging limitations of viral delivery systems and can be used for multiplexed epigenetic editing of a genome.

Control Of Chimeric Antigen Receptor Activation By Their Hinge And Transmembrane Domains

UCSF inventors have created a hybrid sequence that, when engineered into Chimeric Antigen Receptor (CAR) T cells, promotes activation of the cells solely with CD28 antibodies or CD28 ligands. The sequence is a combination of the CD28 or IgG4 hinge region and the CD28 transmembrane, and represent a new opportunity to control T cell function. The technology has been tested in vitro with in vivo studies ongoing. The added functionality through this sequence has potential to promote survival and homeostasis of CAR T cells in the absence of CAR target and improve the specificity and toxicity profiles of current CAR T therapies. 

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).  

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.  

One-Pot Multienzyme Synthesis of Sialidase Reagents, Probes and Inhibitors

Researchers at the University of California, Davis, have developed an environmentally friendly one-pot multienzyme (OPME) method for synthesizing sialidase reagents, probes, and inhibitors.

Small Molecules for Treating Clostridium perfringens-related Bacterial Infections

Researchers at the University of California, Davis have developed a method of treating infections caused by Clostridium perfringens bacteria - via inhibiting the bacteria’s normal quorum sensing processes.

Digital Droplet Infusion System for High-Precision, Low-Volume, Delivery of Drugs or Nutritional Supplements

Researchers at the University of California, Davis have developed the first, digital, droplet infusion system capable of high-precision delivery of very low-volume therapeutics or nutraceuticals.

COVID-19 Risk Factor Biomarker and Prophylactic

Prof. Declan McCole and colleagues from the University of California, Riverside have identified a loss of function PTPN2 variant biomarker that may identify patients who are susceptible to SARS-CoV-2 infection. These patients have increased expression of ACE2, the receptor for SARS-CoV-2. Increased ACE2 has been tied with increased susceptibility to SARS-CoV-2. By identifying patients who are susceptible to SARS-CoV-2 infection, healthcare workers may reduce these patients’ risk of infection by prophylactically administering JAK inhibitors. Currently there is a debate in the medical community on whether or not patients should discontinue their JAK inhibitor therapies.  Clinicians believe that JAK inhibitors could decrease a patient’s immune response to fight COVID.  However these new findings suggest that ACE2 expression is decreased in individuals on a JAK inhibitor therapy. The findings detailed in this section suggests that patients can maintain their JAK inhibitor treatment since it can reduce expression of the receptor required by SARS-CoV-2 to cause infection. Fig 1: Lung epithelial cell line with PTPN2 knockdown (KD) facilitates entry of virus like particles (VLP) expressing the SARS-CoV-2 spike S protein. "(S)" is the SARS-CoV-2 spike protein with no additional protein. "(G)" is the positive control with the rhabdovirus vesicular stomatitis virus. ‘Ctr’ is the control lung epithelial cell.

A Gene Therapy for treating Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a predominantly genetic-based heart disease characterized by right but also recently left ventricular dysfunction, fibrofatty replacement of the myocardium leading to fatal/severe ventricular arrhythmias leading to sudden cardiac death in young people and athletes. ARVC is responsible for 10% of sudden cardiac deaths in people ≥65 years of age and 24% in people ≤30 years of age. ARVC is thought to be a rare disease as it occurs in 1 in 1000-5000 people, although the prevalence may be higher as some patients are undiagnosed or misdiagnosed due to poor diagnostic markers. Growing evidence also reveals earlier onset since pediatric populations ranging from infants to children in their teens are also particularly vulnerable to ARVC, highlighting the critical need to identify and treat patients at an earlier stage of the disease. At present there are no effective treatments for ARVC nor has there been any randomized clinical trials conducted to examine treatment modalities, screening regimens, or medications specific for ARVC. As a result, treatment strategies for ARVC patients are directed at symptomatic relief of electrophysiological defects, based on clinical expertise, results of retrospective registry-based studies, and the results of studies on model systems. The current standard of care is the use of anti-arrhythmic drugs (sotalol, amniodarone and beta-blockers) that transition into more invasive actions, which include implantable cardioverter defibrillators and cardiac catheter ablation, if the patient becomes unresponsive or intolerant to anti-arrhythmic therapies. However, current therapeutic modalities have limited effectiveness in managing the disease, 40% of ARVC patients (a young heart disease) die within 10-11 years after initial diagnosis, highlighting the need for development of more effective therapies for patients with ARVC.

Treatment Of Inherited Retinal Disease

Researchers at UCI have developed a method of treating inherited retinal diseases, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa, by gene therapy of the RPE65 nonsense mutation. This method uses base editor-mediated genome-editing by viral delivery and lead to improved patient treatment through enhanced editing of single base pairs and reduced off-target genomic editing.

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