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Multifunctional Separations Using Adsorbent-Based Membranes

The selective separation of trace components of interest from various mixtures (e.g., micropollutants from groundwater, lithium or uranium from seawater, carbon dioxide from air) presents an especially pressing technological challenge. Established materials and separation processes seldom meet the performance standards needed to efficiently isolate these trace species for proper disposal or re-use. To address this issue, researchers at UC Berkeley developed a novel separation strategy in which highly selective and tunable adsorbents or adsorption sites are embedded into membranes. In this approach, the minor target species are selectively captured by the embedded adsorbents or adsorption sites while the species transport through the membrane. Simultaneously, the mixture can be purified through traditional membrane separation mechanisms. As a proof-of-concept, the researchers incorporated Hg2+-selective adsorbents into electrodialysis membranes that can simultaneously capture Hg2+ via an adsorption mechanism while desalinating water through an electrodialysis mechanism. Adsorption studies demonstrated that the embedded adsorbents maintain rapid, selective, regenerable, and high-capacity Hg2+ binding capabilities within the membrane matrix. Furthermore, when inserted into an electrodialysis setup, the composite membranes successfully capture all Hg2+ from various Hg2+-spiked water sources while permeating all other competing cations to simultaneously enable desalination. Finally, using an array of other ion-selective adsorbents, the Berkeley team showed that this strategy can in principle be applied generally to any target ion present in any water source. This multifunctional separation strategy can be applied to existing membrane processes to efficiently capture targeted species of interest, without the need for additional expensive equipment or processes such as fixed-bed adsorption columns.

COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS

As of June 2020, the pandemic caused by SARS-CoV-2 infections (Coronaviral Disease 2019 (Covid-19)) caused about 9 million infections and about 460,000 deaths worldwide. The pandemic is expected to expand in the late 2020, particularly, because of the lack of a therapeutically effective treatment for the disease.   UC Berkley researchers have discovered compositions and methods treating an RNA virus infection such as SARS-CoV-2 infections by administering combined effective amounts of an RNA-dependent RNA polymerase inhibitor, such as remdesivir, and a second therapeutic agent for treating infection with an RNA virus.

METHODS OF TREATING SARS-COV-2 INFECTION USING INHIBITORS OF LIPOGENESIS

As of June 2020, the pandemic caused by SARS-CoV-2 infections (Coronaviral Disease 2019 (Covid-19)) caused about 9 million infections and about 460,000 deaths worldwide. The pandemic is expected to expand in the late 2020, particularly, because of the lack of a therapeutically effective treatment for the disease. Therefore, methods of treating SARS-CoV-2 infection are desired.   UC Berkeley inventors have developed methods of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2 by administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis. The inhibitor of lipogenesis can be an inhibitor of a lipogenic enzyme or an activator of 5’AMP-activated protein kinase (AMPK).  

COMPOSITIONS AND METHODS FOR INCREASING HOMOLOGY-DIRECTED REPAIR

Molecular self-assembly with scaffolded DNA origami offers a route for folding nucleic acid molecules in user-defined ways, to generate DNA nanostructures. DNA nanostructures have a single-stranded DNA that is folded into distinct shapes via oligonucleotides termed “staples.” Engineered nuclease systems can be used to cleave a target DNA at a specified location. Examples of engineered nuclease systems include TALENs, zinc finger nucleases, mega-nucleases, and CRISPR-Cas systems. Introduction of a break in a nucleic acid (e.g. genome) can facilitate the introduction of a donor nucleic acid.    UC Berkeley researchers have discovered compositions comprising a gene-editing polypeptide, a single-stranded donor DNA, and one or more staple oligonucleotides which can be used for gene editing. 

Composition and Methods of a Nuclease Chain Reaction for Nucleic Acid Detection

This invention leverages the nuclease activity of CRISPR proteins for the direct, sensitive detection of specific nucleic acid sequences. This all-in-one detection modality includes an internal Nuclease Chain Reaction (NCR), which possesses an amplifying, feed-forward loop to generate an exponential signal upon detection of a target nucleic acid.Cas13 or Cas12 enzymes can be programmed with a guide RNA that recognizes a desired target sequence, activating a non-specific RNase or DNase activity. This can be used to release a detectable label. On its own, this approach is inherently limited in sensitivity and current methods require an amplification of genetic material before CRISPR-base detection. 

COMPOSITIONS AND METHODS FOR IDENTIFYING HOST CELL TARGET PROTEINS FOR TREATING RNA VIRUS INFECTIONS

Viral infection is a multistep process involving complex interplay between viral life cycle and host immunity. One defense mechanism that hosts use to protect cells against the virus are nucleic-acid-mediated surveillance systems, such as RNA interference-driven gene silencing and CRISPR-Cas mediated gene editing. Another important stage for host cells to combat virus replication is translational regulation, which is particular important for the life cycle of RNA viruses, such as Hepatitis C virus and Coronavirus.  While efforts to characterize structural features of viral RNA have led to a better understanding of translational regulation, no systematical approaches to identify important host genes for controlling viral translation have been developed and little is known about how to regulate host-virus translational interaction to prevent and treat infections caused by RNA viruses.   UC Berkeley researchers have developed a high-throughput platform using CRISPR-based target interrogation to identify new therapeutics targets or repurposed drug targets for blocking viral RNA translation.  The new kits can also be used to identify important domains within target proteins that are required for regulating (viral RNA translation) and can inform drug design and development for treating RNA viruses.

Anti-Acinetobacter Baumannii Polyclonal Antibody (AB-pAb)

The inventors have constructed a polyclonal antibody (pAb) for the specific detection of the multi-drug resistant (MDR) bacterial pathogen, Acinetobacter baumannii (A. baumannii), producing the antibody entitled, 'AB-pAb'. The AB-pAb was raised against a recombinant (His-tagged) 22 kDa outer membrane protein (OMP22), an antigenic protein which is conserved across the species. The gene encoding OMP22 was amplified from the clinical A. baumannii isolate, AR_0056, which belongs to the international clonal lineage II, a lineage associated with outbreaks worldwide. The AB-pAb is capable of recognizing purified, denatured, OMP22 by Western blot, in addition to the native protein in whole cells of A. baumannii in vitro. The pAb was optimized for diagnostic use by, firstly, removing antibodies within the heterogeneous pAb pool which were cross-reactive to other, clinically-relevant Gram-negative bacteria (GNB). This eliminates the issue of cross-reactivity often associated with polyclonal antibodies, which can limit their use as diagnostic tools. Moreover, testing was performed under conditions which mimic those of the blood and urine, further enhancing the novel AB-pAb's ability to recognize target bacteria in patient samples. When tested against a panel of clinical isolates by indirect-ELISA, for the recognition of A. baumannii from other clinically relevant GNB, the optimized AB-pAb had a sensitivity of 85.5% (95 % confidence interval: 76.11% to 92.3%) and a specificity of 99.5% (95 % confidence interval: 99.53% to 99.99%) at a cutoff, signal-to-noise ratio (SNR) of 0.1275. To our knowledge, no commercial anti-A. baumannii pAbs are currently available which target OMP22, specifically optimized for diagnostic purposes.

Chimeric Cas9 Variants With Novel Engineered Enzymatic Activities

In this invention, the HNH domain of a Cas9 is replaced by a domain that could have diverse enzymatic activities. This invention enables engineering of Cas9 chimeras that possess novel, conformation-sensitive enzymatic activity to perform specific genome editing in vitro, in vivo, and ex vivo.Prior to this invention, all of the strategies to engineer Cas9 fusion proteins and provide Cas9 with non-natural enzymatic activity for genome manipulations were engineered by fusing specific domains to the N- or C-terminus of Cas9 via long and flexible linkers, or through domain insertion approach. The disadvantages of these synthetic Cas9 chimeras are that the attached domain is on the long flexible linker, and it is very dynamic. Thus, these fusions have a broad activity window and they are large, which makes it difficult to deliver them to the cells. 

Decorating Chromatin for Precise Genome Editing Using CRISPR

A novel fusion construct that fuses Cas9 to a truncated version of human PRDM9 with the purpose of improving precise genome editing via homologous direceted repair (HDR). PRDM9 is a protein that deposits histone marks H3K4me3 and H3K36me3 simultaneously during meiosis to mark recombination hot spots where crossover occurs and is resolved by homologous recombination. H3K36me3 has also been demonstrated to be required upstream of homologous recombination repair after double stranded breaks (DSBs) and during V(D)J recombination for adaptive immunity. Recent evidence suggests PRDM9 acts as a pioneer factor opening closed chromatin. The newly engineered PRDM9C-Cas9 fusion construct shows increased HDR and decreased non-homologous end joining mediated insertions and deletions (indels).

Steroid Regulation Of Inwardly Rectifying K+ Channel As Therapeutics Tool

UC Berkeley researches have discovered a new physiological modality of a potassium channel that is linked to the process of fluid regulation in the brain and is expressed in the choroid plexus (CP) and retinal pigment epithelia. CP is the main producer of cerebrospinal fluid that serves as a buffer to protect the brain, provides it with nutrients and removes waste products. The researchers have shown that application of progesterone resulted in strong potentiation of the inwardly rectifying potassium channel. The potentiation was progesterone-specific and independent of other known membrane progesterone receptors expressed in CP. 

Small Cas9 Protein Inhibitor

A new protein that is able to inhibit the Cas9 protein from Streptococcus iniae (SinCas9). SinCas9 is capable of robust DNA cleavage and offers an immune orthogonal Cas9 for use in gene editing in human cells. The inhibitor is a small protein from a phage and is capable of inhibiting SinCas9 activity in vitro and in human cell genome editing experiments.

Novel Phage CRISPR-Cas Effectors and Uses Thereof

UC Berkeley researchers have discovered a novel family of proteins denoted Cas12L within the Type V CRISPR Cas superfamily distantly related to CasX, CasY and other published type V sequences.  These Cas12L proteins utilize a guide RNA to perform RNA-directed cleavage of DNA.

Single Conjugative Vector for Genome Editing by RNA-guided Transposition

The inventors have constructed conjugative plasmids for intra- and inter-species delivery and expression of RNA-guided CRISPR-Cas transposases for organism- and site-specific genome editing by targeted transposon insertion. This invention enables integration of large, customizable DNA segments (encoded within a transposon) into prokaryotic genomes at specific locations and with low rates of off-target integration.

Multiphoton Magnetic Resonance Imaging

UC Berkeley researchers have developed novel imaging techniques with the use of a multiphoton magnetic resonance imaging apparatus. By taking a particular rotating frame transformation the researchers found that multiphoton excitations appear just like single‐photon excitations and can also use concepts explored in standard single‐photon excitation. One prototype included a low frequency coil while another prototype included no additional hardware but instead used oscillating gradients as a source of extra photons for excitation.  The methods and multiphoton MRI can be used to transform a standard slice selective adiabatic inversion pulse into a multiband version without modifying the RF pulse itself. The addition of oscillating gradients creates multiphoton resonances at multiple spatial locations and allows for adiabatic inversions at each location.

Brown Adipose Tissue Myosin II Activators for Metabolic Therapy

The inventors have uncovered a novel brown adipose tissue (BAT) activation pathway based on cellular tension generated by actomyosin. Initial tests of predicted myosin II activators show the ability to increase the expression of uncoupling protein 1 (UCP1), a pivotal determinant of uncoupled respiration, in murine and human brown and beige cells. This strategy could be the foundation for a novel strategy to treat obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease.

Cellular Potassium Imaging Using A Ratiometric Fluorescent Sensor

The inventors developed a ratiometric fluorescent small molecule probe for potassium ion detection composed of a duo-fluorophore system (KR-1). UV-vis detector and fluorometer measurement support ratiometric response of the probe towards potassium ion concentration. The probe was further applied to cellular potassium level detection using confocal microscope imaging technique. KR-1 enables simple determination of potassium levels in various cancer or non-cancer cell lines.

Covalent Organic Framework With Exceptional Water Sorption Properties

A new covalent organic framework (COF) with defective square lattice topology and exceptional water sorption properties stemming fro its unique framework structure. The COF exhibits a working capacity of 0.23 g(H2O)/g(COF) between 20 and 40% relative humidity without displaying hysteretic behavior. Furthermore, it maintains these promising water sorption properties after several uptake and release cycles. This material could be used as a sorbent for water harvesting or other water sorption related applications.

Improved Cas12a Proteins for Accurate and Efficient Genome Editing

Mutated versions of Cas12a that remove its non-specific ssDNA cleavage activity without affecting site-specific double-stranded DNA cutting activity. These mutant proteins, in which a short amino acid sequence is deleted or changed, provide improved genome editing tools that will avoid potential off-target editing due to random ssDNA nicking.

Traceless Linker for Aliphatic Amines that Rapidly and Quantitatively Fragment

The inventors have developed a traceless linker (TRAILER), which can for the first time modify aliphatic amines and release them rapidly and quantitatively after disulfide reduction. TRAILER can reversibly modify the lysine residues on the Cas9 protein, with the cell penetrating peptide Arg10, and is able to generate a self-delivering Cas9 RNP that can edit cells without transfection reagents.Reduction sensitive linkers have the potential to transform the field of drug delivery due to their ease of use and selective cleavage in intracellular environments. However, despite their compelling attributes, using reduction sensitive linkers for biomolecule conjugation reactions has been challenging in the past, because linkers have not been developed that can efficiently modify aliphatic amines and release them rapidly and completely after reduction. Previous efforts to develop reduction sensitive self-immolative linkers for aliphatic amines have been stymied due to their poor leaving group ability and high pKa values. 

DEVICES AND METHODS FOR GENERATING OLIGODENDROCYTE PROGENITOR CELLS

The emergence of several cell based therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective small molecule or biologic based therapy. Stem cells – including adult and pluripotent subtypes – offer tremendous clinical promise for the treatment of a variety of degenerative diseases, as these cells have the capacity to self-renew indefinitely and to mature into functional cell types and thereby serve as a source of cell replacement therapies (CRTs) and pluripotent stem cells (hPSCs) are of increasing interest for the development of CRTs because of their capacity to differentiate into all cell types in an adult, for which adult tissue-specific stem cells may in some cases not even exist. One potential CRT enabled by hPSCs is oligodendrocyte progenitor cells (OPCs) for the treatment of spinal cord injury (SCI). Such hPSC-OPCs have recently advanced to a Phase II clinical trial and are even being considered for additional diseases in the central nervous system (CNS), such as multiple sclerosis (MS), or injury from radiation.   UC researchers have developed a microscale 3D culture screening and analysis methodology that is relevant to the production of several up and coming cell replacement therapy candidates for which derivation from a precursor cell type requires searching through a large in vitro design space of doses, durations, dynamics, and combinations of signaling cues over several weeks of culture, such as oligodendrocyte progenitor cells (OPCs) and midbrain dopaminergic neurons (mDA neurons) derived from human pluripotent stem cells. 

Strongly Interacting Magnetic Particle Imaging

Nuclear medicine is a diagnostic imaging method that works very well, but it is both expensive and gives off excess radiation. X-rays also are used for diagnostic imaging but have poor contrast. Magnetic Particle Imaging (MPI)is a promising new tracer modality with zero attenuation in tissue, near-ideal contrast and sensitivity, and an excellent safety profile, however, the spatial resolution of MPI is currently the modality’s only weak technical attribute. UC Berkeley and UF researchers have developed a novel, compact, and intuitive MPI scanner that resolves this issue.  The research demonstrated proof-of-concept studies for an MPI modality, referred to herein as strongly-interacting magnetic particle imaging (siMPI) that enables a super-resolution breakthrough. The siMPI provided more than a 6-fold improvement in every dimension of space spatial resolution and 37-fold increase in sensitivity. The MPI can be used for early-stage detection of cancer, gut bleeds, strokes, pulmonary embolism, and tracking immunotherapies and MPI can penetrate any tissue, including bone, lungs, and dense breast tissue.

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF

The CRISPR-Cas system is now understood to confer bacteria and archaea with acquired immunity against phage and viruses. CRISPR-Cas systems consist of Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a CRISPR array, which includes direct repeats flanking short spacer sequences that guide Cas proteins to their targets.  Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. The programmable nature of these minimal systems has facilitated their use as a versatile technology that is revolutionizing the field of genome manipulation.  Current CRISPR Cas technologies are based on systems from cultured bacteria, leaving untapped the vast majority of organisms that have not been isolated.  There is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).     UC Berkeley researchers discovered a new type of Cas 12 protein.  Site-specific binding and/or cleavage of a target nucleic acid (e.g., genomic DNA, ds DNA, RNA, etc.) can occur at locations (e.g., target sequence of a target locus) determined by base-pairing complementarity between the Cas12 guide RNA (the guide sequence of the Cas12 guide RNA) and the target nucleic acid.  Similar to CRISPR Cas9, Cas12 enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.    

Lipid A-Free Caulobacter Crescentus

The inventors generated a mutant of the non-pathogenic, Gram-negative bacterium Caulobacter crescentus that survives in the absence of the protein LpxC. Since LpxC catalyzes an early step in the biosynthesis of Lipid A, this strain appears to have no Lipid A by several measures. The Limulus Amoebocyte Lysate assay detected only background levels of Lipid A in the lpxC deletion mutant, and lipid species with the characteristics of Caulobacter lipid A were not detectable by mass spectrometry. This mutant is only the fourth Gram-negative bacterium, in which wild-type cells have lipid A, where a mutant has been found to survive in the absence of lipid A. Unlike the other lipid A-free species, Caulobacter is not pathogenic, and there is a wealth of genetic tools for modifying it. Lipid A is also known as endotoxin, which can cause septic shock if introduced into the bloodstream of humans. Therefore, any biopharmaceuticals must be extensively processed to remove endotoxin before use as drugs. Lipid A-free Caulobacter could serve as an advantageous alternative platform for the production of biopharmaceuticals, including proteins and even whole-cell preparations, since endotoxin would not have to be removed from the product.

Targeted Ionophore-Based Metal Supplementation

Metal deficiency is implicated in a variety of genetic, neurological, cardiovascular, and metabolic diseases. Current approaches for addressing metal deficiency rely on generic metal ion supplementation, which can potentially lead to detrimental off-target metal accumulation in unwanted tissues and subsequently trigger oxidative stress and damage cascades. The inventors have developed a new modular platform for delivering metal ions in a tissue-specific manner and demonstrate liver-targeted copper supplementation as a proof of concept of this strategy. Specifically, the inventors designed and synthesized a N-acetylgalactosamine-functionalized ionophore, Gal-Cu(gtsm), to serve as a copper-carrying “Trojan Horse” that targets liver-localized asialoglycoprotein receptors (ASGPRs) and releases copper only after being taken up by cells, where the reducing intracellular environment triggers copper release from the ionophore. The inventors utilized a combination of bioluminescence imaging and inductively-coupled plasma mass spectrometry assays to establish ASGPR-dependent copper accumulation with this reagent in both liver cell culture and mouse models with minimal toxicity. The modular nature of this synthetic approach presages that this platform can be expanded to deliver a broader range of metals to specific cells, tissues, and organs in a more directed manner to treat metal deficiency in disease. This patent broadly covers directed metal delivery to select organs, tissues, and organelles.

Simultaneous Detection Of Protein Isoforms And Nucleic Acids From Low Starting Cell Numbers

Embryo-specific nucleic acid modifications, including retrotransposon activity-derived genomic modifications and alternative splicing of mRNA, is crucial for the development of mammalian embryos. However, determining if all genomic modifications and mRNA isoforms translate to protein variations remain intriguing questions due to difficulty in measuring protein isoforms and nucleic acids from small starting cell numbers.    UC Researchers have developed a system for performing dual nucleic acid and protein isoform measurements on low starting cell numbers equivalent to the number of blastomeres composing early embryonic development stages (morula and blastocysts).  The system integrates fractionation polyacrylamide gel electrophoresis (fPAGE) with off-chip analysis of nucleic acids in the nuclei. An additional method can be used to remove nuclei for off-chip analysis. The system can measure expression of protein isoforms from the cytoplasmic fraction of 1-100 cells while achieving analysis of either DNA or mRNA retained in the nuclei. The researchers have demonstrated signal from immunoprobed protein correlates strongly with protein expression prior to lysis in TurboGFP-expressing cells and that mRNA levels correlate with protein abundance in TurboGFP-expressing cells.

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