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Generalizable and Non-genetic Approach to Create Metabolically-active-but-non-replicating Bacteria

Researchers at the University of California, Davis have developed a method to stop bacterial growth while maintaining desirable metabolic functions for therapeutic and biotechnological applications.

Teixobactin O-Acyl Isopeptide Prodrugs

Recently, teixobactin was investigated to treat antibiotic-resistant pathogens, but the drug has yet to reach clinical trial due to its tendency to form gels which prevents accurate dosing. To address this, researchers at the University of California, Irvine have invented a new library of teixobactin related prodrugs which show improved solubility and efficacy versus teixobactin.

A Broadly Neutralizing Molecule Against Clostridium Difficile Toxin B

Researchers at UCI have developed a family of recombinant protein therapeutics against Clostridium difficile designed to provide broad-spectrum protection and neutralization against all isoforms of its main toxin, TcdB. These antitoxin molecules feature fragments of TcdB’s human receptors (CSPG4 and FZD) which compete for TcdB binding, significantly improving upon existing antibody therapeutics for Clostridium difficile infections.

(2022-099) Repeat expansion disease therapy with antisense RNA vectors

Alternative splicing accounts for a considerable portion of transcriptomic diversity, as most protein-coding genes are spliced into multiple mRNA isoforms. However, errors in splicing patterns can give rise to mis-splicing with pathological consequences, such as the congenital diseases familial dysautonomia, Duchenne muscular dystrophy, and spinal muscular atrophy. Small nuclear RNA (snRNA) components of the U snRNP family have been proposed as a therapeutic modality for the treatment of mis-splicing. U1 snRNAs offer great promise, with prior studies demonstrating in vivo efficacy, suggesting additional preclinical development is merited. Improvements in enabling technologies, including screening methodologies, gene delivery vectors, and relevant considerations from gene editing approaches justify further advancement of U1 snRNA as a therapeutic and research tool.

(SD2022-270) Algorithm for de novo drug discovery

Generation of drug-like molecules with high binding affinity to target proteins remains a difficult and resource-intensive task in drug discovery. Existing approaches primarily employ reinforcement learning, Markov sampling, or deep generative models guided by Gaussian processes, which can be prohibitively slow when generating molecules with high binding affinity calculated by computationally-expensive physicsbased methods. In drug discovery, a common paradigm today involves performing an initial high-throughput experimental screening of available compounds to identify hit compounds, which is both resource-intensive and can only identify which existing compounds are promising, relying on the further work of medicinal chemists to optimize these hit compounds into lead compounds. As an alternative, many computational methods have been proposed for de novo drug design, including genetic algorithms and other deep learning-based approaches. Methods outside of deep learning are generally not flexible enough to be entirely useful in drug discovery, while current state-of-the-art deep learning methods are either prohibitively slow or cannot generate molecules with an adequate level of desirability.

Human Antibody Targeting Cd146 And Uses Thereof

Brief description not available

(SD2020-085) Targeting RBP-Prss23 Binding Interaction For Myc-Dependent Cancer Therapy. Therapeutic for Myc-dependent cancer.

Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A. The linkages between m6A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukaemiaC-MYC(MYC) was among of the earliest described human oncogenes identified and is now recognized as the primary driver in oncogenic transformation and maintenance of cancer gene expression programs in a broad spectrum of cancer types where cells become “addicted” and dependent on MYC for survival. MYC transcript stability is coordinately regulated by RNA-binding proteins that both positively and negatively affect its half-life. Several RBPs interacting with m6A-modified RNA become upregulated in cancer, and are required for cellular growth, survival and invasion of cancer cells. Thus, Myc regulates cellular function and survival in part by modulating RNA metabolism and is itself controlled posttranscriptionally by RBPs.There have been conflicting findings regarding the function of YTHDF2 in cancer. For example, loss of YTHDF2 sensitizes acute myeloid leukemia (AML) cells to TNF-induced apoptosis, while overexpression of YTHDF2 in hepatocellular carcinoma (HCC) represses cell proliferation and growth by destabilizing EGFR mRNA [9, 10]. Moreover, the direct YTHDF2 target RNAs have yet to be defined in the mammary epithelial or in human breast cancer. It is unknown if the mechanism in other cancer types may be attributed to YTHDF2-Prss23 regulation. Existing art includes US20100104501A1 patent, characterizing Prss23 as a biomarker, therapeutic and diagnostic target. The invention involves compounds which bind to and/or inhibit the activity of PRSS23, which is the opposite of what we have determined is required to trigger apoptosis in Myc-dependent cancer.There are no current findings suggesting intervention of the YTHDF2-Prss23 binding interaction as a cancer therapeutic.

CRISPR-Cas Inhibiting Polypeptides

Brief description not available

Epigenetic Prevention and Treatment of CDKL5 Deficiency Disorder

Researchers at the University of California, Davis have developed a targeted epigenetic approach for the prevention and treatment CDKL5 deficiency disorder.

CRISPR-Cas Effector Polypeptides and Methods of Use Thereof

CRISPR-Cas systems comprise a CRISPR-associated (Cas) effector polypeptide and a guide nucleic acid. Such CRISPR-Cas systems can bind to and modify a targeted nucleic acid. The programmable nature of these CRISPR-Cas effector systems has facilitated their use as a versatile technology for use in, e.g., gene editing.   UC Berkeley researchers have discovered new CRISPR-Cas effector Cas12L/Cas Lambda/Casλ polypeptides and methods of modifying a target nucleic acid using a Cas12L/Cas Lambda polypeptide.

Compositions and Methods for Treating Viral Infections

Researchers at the University of California, Davis (“UC Davis”) have developed methods for screening and targeting regions of viral genomes to identify drugs that inhibit the replication of RNA viruses.

Methods and Compositions for the Treatment of Huntington's Disease

There are no approved disease-modifying therapies for Huntington’s disease (HD), a fatal neurodegenerative condition caused by a heterozygous expansion of a CAG array in exon 1 of Huntingtin (Htt). Typically, HD patients are heterozygous for the toxic gain of function disease allele, yet expression of the wildtype version of the gene is essential. The inventors have developed methods and compositions to selectively silence expression from the disease-associated allele while leaving the wildtype version intact. The invention relies on the introduction of a 'poison' exon into the diseased allele wherein introduction of the poison exon may be accomplished by standard methods in the art, such as introduction of the exon sequences through homology-directed repair following targeted nuclease cleavage, transposon-associated targeted sequence introduction, base editing, and prime editing. Following the introduction of the poison exon, post-transcriptional splicing results in an RNA that is susceptible to nonsense mediated decay due to the introduction of a stop codon in the introduced exon. RNAs comprising the poison exon are subsequently degraded in the cell, effectively silencing expression of the mutant disease-associated allele.

COMPOSITIONS AND METHODS FOR REDUCING RNA LEVELS

Human diseases that follow a dominant negative inheritance pattern present a great challenge for treatment using gene therapy methods. In such cases, a copy of an allele is inherited from each parent: one is a pathogenic allele causing a disease phenotype (e.g., by exerting a toxic, gain-of-function effect) and the other is a wild-type (non-pathogenic) allele. Allele-specific targeting is especially important when the wild-type allele is crucial to normal function, e.g., the wild-type allele encodes a protein whose function is critical. There is therefore a need for compositions and methods of allele-specific gene editing.   UC Berkeley researchers have created methods and systems for reducing the level of an RNA transcript from a target nucleic acid in an allele-specific manner. Such systems and methods can be used to treat a disease that results from or is caused by a toxic gain-of-function protein.   

(SD2022-010) Method for transmembrane protein semisynthesis and reconstitution in lipid membranes

Cellular lipid membranes are embedded with transmembrane proteins crucial to cell function. Elucidating membrane proteins’ diverse structures and biophysical mechanisms is increasingly necessary due to their growing prevalence as a therapeutic target and sheer ubiquity in cells. Most biophysical characterization strategies of transmembrane proteins rely on the tedious overexpression and isolation of recombinant proteins and their reconstitution in model phospholipid bilayers.Unfortunately, membrane protein reconstitution depends on the use of denaturing and unnatural detergents that can interfere with protein structure and function. We have developed a detergent‐free method to reconstitute transmembrane proteins in model phospholipid vesicles and GUVs. Additionally, transmembrane proteins are difficult to express in cells due to the extreme insolubility of their transmembrane domain. By incorporating a synthetic transmembrane peptide into liposomes and simply expressing soluble portions of transmembrane proteins in cells, we can use this semisynthetic ligation strategy to more easily construct functional transmembrane proteins and reconstitute them into liposomes for biophysical and biochemical studies.Inteins can be found contiguously or non contiguously within some proteins. Non‐contiguous inteins are called “split inteins”. Inteins can be thought of as a type of protein intron which splices itself out of proteins. When non‐contiguous inteins find and bind to each other, they are then able to excise themselves resulting in the ligation of their respective exteins. Split intein pairs (C‐intein and N‐intein) can be attached to proteins of interest in synthetic and cellular systems to ligate protein sequences together.

Anti-Influenza Small Molecule Therapy

Professor Jiayu Liao from the University of California, Riverside has identified small molecules that block  the Influenza B virus (IBV) from replicating by inhibiting the SUMOylation pathway. This IBV virus replication inhibition works by using the novel SUMOylation inhibitor, STE025, to inhibit the SUMOylation of the IBV M1 protein. SUMOylation also has active roles in the pathogenesis of several diseases, such as tumorigenesis, neurodegenerative diseases and infections, and as such, this technology could potentially be applied to these types of diseases as well. Fig 1: Cell death induced by IBV infection can be rescued by the UCR SUMOylation-specific inhibitor, STE025 (blue) compared to cells not exposed to IBV (green), and cells exposed to IBV without the UCR inhibitor (purple and red).  

Methods of Treating the Metabolic Syndrome, NAFLD/NASH and Type 2 Diabetes

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major source of liver disease globally. Clinically, NAFLD describes a spectrum of hepatic events ranging from moderate lipid accumulation to more aggressive steatosis with associated inflammation, ballooning hepatocytes, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma (HCC). The excessive accumulation of lipids is a major risk factor for disease progression from the clinically silent NAFLD to the inflammatory, fibrotic, and cirrhotic nonalcoholic steatohepatitis (NASH) stage. Thus, there is a need for methods of treating metabolic disorders.   UC Berkeley researchers have discovered compounds that can be used to treat people with metabolic diseases.  

PHAGE-MEDIATED DELIVERY OF GENES TO GUT MICROBIOME

Researchers at UCSF have developed methods to engineer bacteriophage for gene delivery to gut microbiome. 

ENGINEERED ACE2 RECEPTOR TRAPS TO BLOCK SARS-COV-2 INFECTION

Researchers at UCSF and the Chan Zuckerberg Biohub have developed a set of ACE2 variants which potently block SAR-CoV-2 infection in cells. 

Method For Generating Endotoxin-Free Gram-Negative Bacteria

The inventors have discovered that lipid A can be genetically eliminated from Caulobacter crescentus, dependent upon inactivation of the transcriptional regulator Fur and the presence of anionic sphingolipids called ceramide phosphoglycerate. The inventors identified and characterized genes responsible for ceramide phosphoglycerate synthesis. The inventors propose that other Gram-negative bacteria, including E. coli, can be engineered to eliminate lipid A by inactivating their Fur homologs, introducing genes for the synthesis of ceramide phosphoglycerate, or both. Bacteria thus engineered could be used for the endotoxin-free production of small molecule or protein-based pharmaceuticals, therapeutic bacteriophage, RNAs, or endotoxin-free therapeutic bacteria.BACKGROUND The bacterium Escherichia coli is used as a platform for the manufacture of 20-30% of the biopharmaceuticals currently marketed. E. coli, like other Gram-negative bacteria, possesses an outer membrane containing the glycolipid lipopolysaccharide (LPS). The innermost portion of LPS, lipid A, anchors LPS in the outer leaflet of the outer membrane. Lipid A, historically known as endotoxin, is a potent stimulator of the innate immune system in mammals. Even small amounts of endotoxin in the bloodstream can induce an unregulated, systemic inflammatory response known as sepsis. A major hurdle and cost in E. coli-based pharmaceutical production is the removal of endotoxin from each final product. Endotoxin removal strategies are developed on a case-by-case basis to find conditions in which the stable lipid A contaminant can be chemically separated from the desired product while not adversely affecting product recovery or activity. Industrial biotechnology could benefit from additional bacterial production platforms that eliminate the need for extensive processing to remove endotoxins. The challenge is that lipid A is almost always an essential structural component of the OM, meaning that it cannot be eliminated without causing the death of the bacterium. To date, only four species that normally contain lipid A have yielded mutant strains that completely lack lipid A and its biosynthetic precursors. However, these species are not well-developed platforms for industrial biotechnology. An E. coli strain (KPM22) has been developed that survives with only lipid IVA, an intermediate in the lipid A biosynthesis pathway. Lipid IVA contains fewer acyl chains than mature lipid A, causing a ~1000-fold reduction in its endotoxin activity. A modified version of this “endotoxin-free” strain is currently marketed by Lucigen under the trade name ClearColi (https://www.lucigen.com/faq-clearcoli.html).

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