The present disclosure provides methods (referred to herein as “SWITCH-seq”), compositions, kits, and systems for profiling RNA expression in a cell (including, e.g., cells within an intact tissue) in both untargeted and targeted manners. Also provided by the present disclosure are methods for diagnosing a disease or disorder in a subject based on a profile of RNA expression in a cell tissue, or other biological sample. Methods of screening for or testing a candidate agent capable of modulating RNA expression are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder in a subject in need thereof. Oligonucleotides useful for performing the methods described herein are also provided by the present disclosure. Additionally, the present disclosure provides kits comprising any combination of the oligonucleotides described herein.
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
C12Q 1/34 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving hydrolase
C12Q 1/6806 - Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
Disclosed herein are capped RNA transcripts comprising one or more modified nucleotides at position +3 or higher with reference to a 5′ terminus of the RNA molecule, and methods of making the same. Also provided are compositions comprising one or more of the capped RNA transcripts provided herein, and methods of using said compositions for therapeutic applications.
Methods and systems described herein enable robust and facile multi-site base editing through pooled editing, suitable for one-step encoding of information. gRNAs show robust editing in pools and demonstrate simultaneous multi-site editing across >100 genomic sites. Additionally, individual stem cells with more than two dozen edits can be obtained with minimal screening.
The present disclosure provides methods, compositions, and systems for profiling epitranscriptomic RNA modifications in a cell. The present disclosure also provides methods for profiling interactions between one or more RNAs of interest in a cell and an RNA-binding protein (e.g., a protein that introduces an epitranscriptomic modification on an RNA of interest). Also provided by the present disclosure are methods for diagnosing a disease or disorder in a subject based on a profile of epitranscriptomic RNA modifications or a profile of interactions between an RNA binding protein and RNAs in a cell, including cells within an intact tissue. Methods of screening for or testing a candidate agent capable of modulating epitranscriptomic modification of one or more RNAs or interactions between one or more RNAs and an RNA-binding protein are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder in a subject in need thereof. Pairs of probes and sets of probes comprising oligonucleotide portions, which may be useful for performing the methods described herein, are also described by the present disclosure. Additionally, the present disclosure provides kits comprising any of the probes described herein.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
C40B 70/00 - Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or barcodes
5.
Variant Identification in the Presence of Alignment Artifacts
Variant identification in the presence of alignment artifacts is described. Discordant reads of sequencing data may be identified with respect to a reference sequence. A variant-indicative signal may be generated based at least in part on a subread analysis of the discordant reads, the variant-indicative signal including one or both of a discordant junction signal or an alignment generated using a latent breakpoint graph. A variant call may be generated based at least in part on the variant-indicative signal, the variant call identifying a structural variant in the sequencing data as compared to the reference sequence.
Described herein are muscle-specific targeting moieties and compositions including the muscle specific targeting motifs. Also described herein are uses of the muscle-specific targeting motifs and compositions including the muscle specific targeting moieties. In some embodiments, the muscle-specific targeting moieties and compositions including the muscle specific targeting moieties can be used to direct delivery of a cargo to a muscle cell.
The present disclosure provides methods of using a prime editor in combination with prime editing guide RNAs (pegRNAs) and, optionally, nicking gRNAs to carry out prime editing to directly correct mutations (i.e., c.1412delA) in the CDKL5 gene that cause CDKL5 deficiency disorder. The present disclosure also provides compositions, complexes, and systems comprising the pegRNAs, nicking gRNAs, and/or prime editors disclosed herein, as well as polynucleotides and vectors encoding the same, and cells, kits, and pharmaceutical compositions comprising the same.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61P 25/00 - Drugs for disorders of the nervous system
C12N 7/04 - Inactivation or attenuationProducing viral sub-units
Provided herein are methods and compositions for screening of multiple nucleic acid sites, such as functional non-coding transcriptional regulatory elements in a cell. In particular, provided are methods and compositions, comprising: delivering to a cell a composition comprising: a single guide RNA (sgRNA) or a polynucleotide encoding the sgRNA comprising a sequence capable of hybridizing with a target sequence present in a non-coding transcriptional regulatory element, and an effector protein or one or more nucleotide sequences encoding the effector protein optionally comprising an effector domain, wherein the sgRNA hybridizes to the target sequence and forms a complex with the effector protein; and measuring gene expression upon binding of the complex to the target sequence.
The Trustees of Columbia University in the City of New York (USA)
The Broad Institute, Inc. (USA)
Inventor
Quinn, Peter M. J.
Lopes Da Costa, Bruna
Tsang, Stephen H.
Liu, David R.
Abstract
The present disclosure provides systems, methods, and compositions for modifying the crumbs homologue-1 gene. Particularly the present disclosure provides systems, methods, and compositions for prime editing insertion or correction of mutations in the crumbs homologue-1 gene.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61K 38/17 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
The present invention generally relates to compositions, methods applications and screens used in functional genomics that focus on gene function in a cell and that may use vector systems and other aspects related to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas systems and components thereof. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system.
Described in certain example embodiments herein are compositions, such as immunogenic compositions that can contain or more viral polynucleotides and/or polypeptides. In some embodiments, the one or more viral polynucleotide is a non-canonical viral open reading frame (ORF). Also described herein are methods to identify one or more viral polynucleotides and/or polypeptides such as a non-canonical viral ORF, such as massively parallel ribosome profiling.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in prokaryotic and eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity.
Described herein are muscle-specific targeting moieties and compositions including the muscle specific targeting motifs. Also described herein are uses of the muscle-specific targeting motifs and compositions including the muscle specific targeting moieties. In some embodiments, the muscle-specific targeting moieties and compositions including the muscle specific targeting moieties can be used to direct delivery of a cargo to a muscle cell.
In certain aspects, provided herein are mutant stimulator of interferon genes (STING) polypeptides, compositions thereof and methods of using the same, wherein the mutation is within the dimerization interface of the STING, and wherein the mutation reduces the ability of the mutant STING polypeptide to mediate protein leakage across a membrane compared to a wild-type STING polypeptide.
Aspects of the present disclosure generally relate to systems, compositions, and methods for prime editing with improved editing efficiency and/or reduced indel formation by inhibiting one or more genes of interest while conducting prime editing of a target site. Accordingly, the present disclosure provides systems, compositions and methods for editing a nucleic acid molecule by prime editing that involves contacting a nucleic acid molecule with a prime editor, one or more pegRNAs, and an inhibitor of a gene of interest, thereby installing one or more modifications to the nucleic acid molecule at a target site with increased editing efficiency and/or lower indel formation. The present disclosure further provides polynucleotides for editing a DNA target site by prime editing comprising a nucleic acid sequence encoding a napDNAbp, a polymerase, and an inhibitor of one or more genes of interest, wherein the napDNAbp and polymerase is capable in the presence of a pegRNA of installing one or more modifications in the DNA target site with increased editing efficiency and/or lower indel formation. The disclosure further provides, vectors, cells, and kits comprising the compositions and polynucleotides of the disclosure.
The present disclosure provides methods, compositions, and systems for evolving virus-like particles (VLPs) having one or more desired properties such as increased production levels, increased cargo packaging efficiency, and/or increased transduction of particular target cell types of interest. The present disclosure also provides libraries for use in such methods, and methods for producing the libraries. Group specific antigen (gag) proteins comprising nucleocapsid protein variants evolved using the methods described herein are also provided herein. The present disclosure also provides VLPs comprising such gag proteins comprising nucleocapsid protein variants. Polynucleotides, vectors, cells, and kits useful for performing the methods described herein are also provided.
According to some embodiments, the cell culture system allows for the passage of cells in high-throughput cell culture applications. Unlike enzymatic detachment processes, the cell culture system, in some embodiments, limits any imparted damage onto the cell. Additionally, the lack of reliance on enzymes for cell detachments (e.g. trypsin) reduces and/or prevents the accrual of genetic mutations that can occur during enzymatic detachment processes. The cell culture system, in some embodiments, is capable of passaging and/or detaching cells at rates convenient for high throughput cell culturing and/or automated cell culturing regimes. Advantageously, the cell culture system, in certain embodiments, provides sufficient adhesion to promote cell growth and proliferation, but is capable of reducing the adhesion between the cell and the surface upon application of the electric field.
Described herein are compositions for treatment of vaginal dysbiosis (e.g., bacterial vaginosis), symptoms of vaginal dysbiosis (e.g., bacterial vaginosis), or conditions/disorders associated with vaginal dysbiosis (e.g., bacterial vaginosis). Also disclosed herein are methods for treating vaginal dysbiosis (e.g., bacterial vaginosis) in an individual in need thereof, methods for reducing the risk of vaginal dysbiosis (e.g., bacterial vaginosis) in an individual in need thereof, methods for preventing recurrence of vaginal dysbiosis (e.g., bacterial vaginosis) in an individual treated for a prior episode of vaginal dysbiosis (e.g., bacterial vaginosis). Also described are methods for restoring Lactobacillus dominated microbiota, including L. crispatus-dominated microbiota or microbiota dominated by other non-iners Lactobacillus species, in an individual in need thereof.
A61K 31/201 - Carboxylic acids, e.g. valproic acid having a carboxyl group bound to an acyclic chain of seven or more carbon atoms, e.g. stearic, palmitic or arachidic acid having one or two double bonds, e.g. oleic or linoleic acid
A61K 31/7056 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
The subject matter disclosed herein is generally directed to methods for highly multiplexed spatially resolved optical perturbation screening and kits thereof. The methods use sequence specific perturbations that can be amplified in situ and optically decoded. The perturbations can be paired with optically decoded gene expression data.
Described herein are hematopoietic cell-specific targeting moieties and compositions including the hematopoietic cell specific targeting motifs. Also described herein are uses of the hematopoietic cell-specific targeting motifs and compositions including the hematopoietic cell specific targeting moieties. In some embodiments, the hematopoietic cell-specific targeting moieties and compositions including the hematopoietic cell specific targeting moieties can be used to direct delivery of a cargo to a hematopoietic cell.
Systems, methods and composition for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising novel Fanzor polypeptides and a reprogrammable targeting nucleic acid component and methods and application of use are described.
C12N 9/78 - Hydrolases (3.) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
C12Q 1/34 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving hydrolase
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
Engineered, non-naturally occurring, RNA-targeting Type V Cas polypeptides lacking collateral cleavage activity, compositions thereof, CRISPR-Cas systems thereof, packaging and delivery systems thereof, kits thereof, and methods of use thereof, for modifying target RNA. The Type V Cas polypeptide may be a Cas12 polypeptide, optionally a Cas12a2 polypeptide. The compositions may comprise the Type V Cas polypeptide and an engineered polypeptide comprising a tetratricopeptide repeat (TPR) domain, a DUF3800 domain and, optionally, a UvrD polypeptide and an additional TPR polypeptide. CRISPR-Cas systems may comprise the Type V Cas polypeptide, or a composition thereof, and one or more guide molecules.
The present disclosure includes compositions and methods for treating cardiovascular disease (CVD) (e.g., cholesterol related disorders, or diseases caused or characterized by increased levels of plasma triglycerides, plasma cholesterol, or serum C-reactive protein), or symptoms thereof. The disclosure also includes compositions and methods for lowering plasma triglycerides in a subject, lowering plasma cholesterol levels in a subject, and lowering serum C-reactive protein levels in a subject.
This application discloses in part methods and compositions for mutating immune cells (e.g., CAR-T cells) and determining mutated immune cell cancer killing efficacy in vivo.
Multi-scale footprinting of DNA-protein interactions is described. Multi-scale footprint scores may be generated based on chromatin accessibility data, the multi-scale footprint scores indicating protein binding to positions of a genome at different protein size scales. A deep learning model may be trained using the multi-scale footprint scores and corresponding DNA sequences. DNA-protein interactions for a DNA sequence of interest may be predicted using the trained deep learning model. The prediction may include generating sequence attribution scores for the DNA sequence of interest using the trained deep learning model and predicting transcription factor binding sites of the DNA sequence of interest based on the sequence attribution scores.
G16B 5/00 - ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
G16B 40/00 - ICT specially adapted for biostatisticsICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
26.
ELECTROPHILIC REACTIVE LINKERS FOR LABELING OF POLYPEPTIDES AND METHODS OF USE THEREOF
The present disclosure relates to electrophilic reactive linkers, which find utility labeling target substrates according to the formula L1-El, El-L1, or L1-El-L2, wherein El is an electrophilic reactive group and wherein L1 and L2 are linking molecules. Molecules according to the present invention find use, for example, in multifunctional chimeric molecules (e.g., bifunctional molecules), which make substrate modifications such as post-translational modifications to targets that are not the natural substrate; accordingly, diseases or disorders may be treated or prevented with molecules of the present disclosure.
A61K 47/55 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
Provided herein are methods of treating cancers, inflammatory diseases, and autoimmune diseases and methods of modulating related phenotypes and expression levels by targeting interactions among E3 ligases, E3-like proteins, and their interacting partners. Methods of identifying modulators of such interactions are also provided. Also provided herein are cell therapies comprising alterations in at least two members of a co-functional gene module.
C07K 16/00 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences especially for use as to nucleotide repeat disorders. Provided are delivery systems and tissues or organ which are targeted as sites for delivery especially for use as to nucleotide repeat disorders. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex or system especially for use as to nucleotide repeat disorders, as well as methods for the design and of such. Also provided are methods of directing CRISPR complex or system formation in eukaryotic cells especially for use as to nucleotide repeat disorders including with consideration of specificity for target recognition and avoidance of toxicity and editing or modifying a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The invention provides for systems, methods, and compositions for altering expression of target gene sequences and related gene products. Provided are structural information on the Cas protein of the CRISPR-Cas system, use of this information in generating modified components of the CRISPR complex, vectors and vector systems which encode one or more components or modified components of a CRISPR complex, as well as methods for the design and use of such vectors and components. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system. In particular the present invention comprehends optimized functional CRISPR-Cas enzyme systems. In particular the present invention comprehends engineered new guide architectures to be used in optimized CRISPR-Cas enzyme systems.
Described and featured herein are antibodies that specifically bind to a phosphorylated S104 amino acid residue in a CARD9 polypeptide and methods of using such antibodies to identify subjects vulnerable to fungal infection, including fungal infections caused by Candida spp.
Methods and compositions for analysis and treatment of repeat expansion disorders are described. Labeled amplicons of a variable repeat region of a gene may be generated, the generating using primers that introduce at least one molecular label to respective nucleic acid molecules of origin of a biological sample. The labeled amplicons may be sequenced to generate sequencing reads having the at least one molecular label incorporated. A sequence repeat length distribution of the variable repeat region in at least a portion of the biological sample may be generated based on the sequencing reads.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
33.
DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR TARGETING DISORDERS AND DISEASES USING PARTICLE DELIVERY COMPONENTS
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery particle formulations and/or systems comprising one or more components of a CRISPR-Cas system, which are means for targeting sites for delivery. The delivery particle formulations of the invention are preferably nanoparticle delivery formulations and/or systems. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The disclosure includes non-naturally occurring or engineered CRISPR Cas9, each associated with at least one destabilization domain (DD), along with compositions, systems and complexes involving the DD-CRISPR Cas9, nucleic acid molecules and vectors encoding the same, delivery systems involving the same, uses therefor.
Systems, methods and composition for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising novel TnpB polypeptides and a reprogrammable targeting nucleic acid component and methods and application of use are provided.
Electrocardiogram-based deep learning for hypertension prediction is described. An electrocardiogram analysis module may include a data preprocessor configured to normalize an electrocardiogram to generate a standardized input for electrocardiogram-based hypertension prediction. The electrocardiogram analysis module may further include a deep learning model including a neural network trained to identify features associated with hypertension from the standardized input and at least one dense layer trained to generate a hypertension risk prediction based on the identified features. The hypertension risk prediction may comprise a probability score indicating a likelihood of hypertension.
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.
A61K 31/7088 - Compounds having three or more nucleosides or nucleotides
A61K 47/64 - Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C07K 7/06 - Linear peptides containing only normal peptide links having 5 to 11 amino acids
C07K 14/005 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from viruses
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
The invention, in some aspects, includes systems, methods and components of molecular recorders that encode the timing of transcriptional activity into the sequence of RNA, which can then enable a sequencing-based readout of the internal dynamics of cells.
Methods and compositions capable of obtaining paired transcriptome and genotype information from single cells in high throughput are provided. Disclosed methods and compositions obtain paired transcriptome and genotype information from single cells in a manner that is highly sensitive, capable of detecting even very low-level transcripts in single cells, and associating such low-level transcripts and abundance information with associated genotypes, within a single cell.
Systems, methods and compositions for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising IscB polypeptides, novel IscB nucleases and reprogrammable targeting nucleic acid components and methods and application of use are rovided.
The present disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be glycogen synthase kinase 3 (GSK3) inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
The present disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be glycogen synthase kinase 3 (GSK3) inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
A61K 31/4375 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring hetero atom, e.g. quinolizines, naphthyridines, berberine, vincamine
A61K 31/438 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring being spiro-condensed with carbocyclic or heterocyclic ring systems
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
A61K 31/501 - PyridazinesHydrogenated pyridazines not condensed and containing further heterocyclic rings
A61K 31/506 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Compositions and methods for detecting bacterial pathogens containing microbial resistance genes in a sample, as well as methods for selecting a treatment for human infections involving such organisms. The methods involve carrying out a series of reactions in parallel where each reaction involves detecting a bacterial species or resistance gene in a sample using a CRISPR-Cas13a reaction. In some embodiments, the methods involve culturing a blood sample to increase the concentration of bacteria in the sample and/or direct detection of bacterial pathogens and/or microbial resistance genes in a blood sample.
C12Q 1/689 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
Immunogenic compositions comprising one or more peptides, wherein the one or more peptides: are capable of binding to Major Histocompatibility Complex (MHC) class II, and are derived from one or more translation products of SARS-CoV-2. Also provided include methods of treating and preventing diseases using the immunogenic compositions.
Described herein are engineered, non-naturally occurring systems and compositions comprising multimeric CRISPR-Cas complexes comprising a β-CASP polypeptide, a plurality of Cas polypeptides, and a guide molecule, packaging and delivery systems thereof, and methods of use thereof, for modifying target polynucleotides. In addition, described herein are engineered, non-naturally occurring systems and compositions comprising a class of small Cas proteins (Type II-B, II-C, and II-D Cas proteins) and methods of modifying target sequences using the Type II-B, II-C, II-D Cas proteins and systems thereof.
Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of microorganisms. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent microbial infection, or to improve a subject's heath or wellbeing.
The Trustees of Columbia University in the City of New York (USA)
The Broad Institute, Inc. (USA)
Inventor
Pernice, Wolfgang M.
Hirano, Michio
Caicedo, Juan C.
Abstract
The present disclosure relates to a method for generating a training set based on a first set of images and a second set of images, each image having a respective observational environment and a respective feature set. The method includes (a) obtaining, by a generator module, the first set of images and the second set of images; (b) extracting, by the generator module, one or more feature sets from each image in the first set of images; (c) extracting, by the generator module, one or more respective observational environments from each image in the second set of images; (d) deriving, by an encoder module, one or more latent representations from the one or more feature sets extracted from one or more images in the first set of images; (e) deriving, by the encoder module, one or more style codes from the one or more respective observational environment extracted from one or more images in the second set of images; (f) generating, by the generator module, an interventional training distribution having samples including each respective one or more style codes and each one or more latent representations; and, (g) storing, by the generator module, the interventional training distribution training set.
G06T 11/60 - Editing figures and textCombining figures or text
G06V 10/77 - Processing image or video features in feature spacesArrangements for image or video recognition or understanding using pattern recognition or machine learning using data integration or data reduction, e.g. principal component analysis [PCA] or independent component analysis [ICA] or self-organising maps [SOM]Blind source separation
47.
RNA PROGRAMMABLE EPIGENETIC RNA MODIFIERS AND USES THEREOF
The disclosure provides programmable methylation “writers” and demethylation “erasers” for editing the methylation state of RNA targets, e.g., an RNA transcriptome. In particular, the disclosure provides RNA methylation editor polynucleotide constructs and vectors comprising (i) an RNA programmable RNA binding domain (RNApRNAbd); and (ii) an effector domain, wherein the effector domain is capable of adding or removing a methyl group in an RNA. The disclosed RNA methylation editor constructs are capable of achieving limited off-target modifications in RNA molecules. Further, the disclosure provides methods for making and using the programmable methylation editors to modifying the methylation state of RNA. The disclosure further provides complexes comprising a methylation writer protein and a guide RNA molecule and complexes comprising a demethylation eraser protein and a guide RNA molecule. The disclosure further provides pharmaceutical compositions and cells comprising the disclosed fusion proteins and complexes.
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
The disclosure relates generally to methods and compositions for cryopreservation and processing of blood for single-cell RNA-sequencing. More particularly, the disclosure relates to methods and compositions for preserving and processing whole blood to enable diagnosing and/or treating sepsis via single-cell RNA sequencing (scRNA-seq). In certain aspects, the methods and compositions disclosed herein may be employed in diagnosis and treatment of subjects having or at risk of having sepsis.
The present disclosure relates to compositions and methods for tracking and spatially localizing a cell-expressed fusion protein within the cell (with the fusion protein optionally associated with a subcellular compartment, organelle, synapse, or the like), in a manner that minimizes any disruptive impact upon the cell, at least until the detection process is initiated. Use of transcriptomics and/or barcode nucleic acid detection is employed to assess both spatial localization of intracellularly tagged fusion proteins and to establish cell-cell connectivity, e.g., in neurons across a synapse, by associating axonal identities with individual neurons at the molecular tag and transcriptome level.
C12Q 1/6874 - Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation [SBH]
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.
A61K 31/7088 - Compounds having three or more nucleosides or nucleotides
A61K 47/64 - Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C07K 7/06 - Linear peptides containing only normal peptide links having 5 to 11 amino acids
C07K 14/005 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from viruses
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
Described herein are methods of generating engineered viral capsid variants. Also described herein are engineered viral capsid variants, engineered viral particles and formulations and cells thereof. Also described herein are vector systems containing an engineered viral capsid polynucleotide and uses thereof.
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA. Aspects of the invention in particular relate to Cpf1 mutants having altered PAM specificity.
Provided herein are computer-implemented methods for assigning maternal or fetal origin to one or more genetic variants in cell free DNA (cfDNA) from a sample from a pregnant mammal, preferably a pregnant human, using a probabilistic model for assigning maternal or fetal origin to genetic variants in DNA from a sample obtained from a pregnant mammal, wherein the model assigns maternal or fetal origin based on a combination of fetal fraction and DNA fragment size.
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
C12Q 1/6806 - Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
C12Q 1/6876 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
G16B 5/00 - ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
G16H 10/40 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for data related to laboratory analysis, e.g. patient specimen analysis
G16H 10/60 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records
G16H 50/30 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indicesICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for individual health risk assessment
55.
CELL-SPECIFIC CIS-REGULATORY ELEMENTS, USES THEREOF, AND METHODS OF GENERATING THE SAME
Described in certain embodiments herein are computer implemented methods, systems, and computer program products that can be used to identify or engineered cell specific cis-regulatory elements (CREs). Also described herein are cell specific CREs and uses thereof.
The embodiments disclosed herein utilize RNA targeting effectors to provide a robust CRISPR-based diagnostic for hemorrhagic fever virus applications. Embodiments disclosed herein can differentiate between hemorrhagic fever viruses that present with similar symptoms, as well as between strains of a hemorrhagic fever virus.
C12Q 1/70 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving virus or bacteriophage
The present disclosure features methods for modifying fertility. In some embodiments, the disclosure provides contraceptive compositions and methods of using the same.
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
mutEGFR
mutEGFR
(D770_N771insSVD)
(D770_N771insNPG,
kinase assay
T790) kinase assay
Example
IC50
IC50
No.
[mol/l]
[mol/l]
1
4.14E−07
6.06E−07
2
4.61E−07
7.51E−07
3
2.84E−06
3.41E−06
4
7.58E−09
1.71E−08
(AA)
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
C12Q 1/6886 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
This disclosure relates to novel PRNP targeting sequences. Novel PRNP targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
60.
ENGINEERED TYPE II CAS POLYNUCLEOTIDES WITH REDUCED IMMUNOGENICITY AND USES THEREOF
Engineered Type II Cas polypeptides with reduced immunogenicity, CRISPR-Cas systems thereof, compositions thereof, delivery systems thereof, and methods of use thereof for modifying target polynucleotides, such as, for example, in cells.
The invention provides for systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system.
The invention provides for systems and methods for inserting large polynucleotides into precise locations in a target polynucleotide. In one aspect, the systems comprise an engineered Type I-D/Tn7 CRISPR-associated transposase system (CAST) comprising a Tn7-like transposase linked to or otherwise capable of associating with a Type I-D CRISPR-Cas complex (Tn7-CAST I-D). In another aspect, the systems comprise a Tn7-like transposase comprising a modular target site selection protein, called TnsF, that may be engineered to reprogram the Tn7-like transposase to facilitate insertion at different sites in a target polynucleotide. In another aspect, the systems comprise a transposon system comprising a tyrosine recombinase which provides for scar-less insertion of large donor sequences into target polynucleotides. Also provided are methods for modifying target polynucleotides using the systems; polynucleotides encoding the systems; delivery systems for delivering the components of the systems; and cells and biological products modified by or modified to include the systems.
Systems and methods for targeted gene modification, targeted insertion, perturbation of gene transcripts, and nucleic acid editing. Novel nucleic acid targeting systems comprise components of CRISPR systems and non-LTR retrotransposon elements.
C07K 14/435 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
C07K 14/465 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from birds
Aspects of the disclosure relate to methods, compositions, and systems for editing an endogenous tRNA into a suppressor tRNA, or alternatively, replacing said endogenous tRNA with a suppressor tRNA with using prime editing. Additional aspects relate to compositions comprising the prime editing machinery, pegRNAs, and/or complexes comprising the prime editor and pegRNA that are capable of editing and/or replacing an endogenous tRNA to yield a suppressor tRNA. In some aspects, the disclosure further relates to polynucleotides encoding one or more nucleic acid sequences encoding the prime editor and/or pegRNA, cells comprising the polynucleotides and complexes comprising the prime editor and pegRNA, kits comprising any one of the compositions, complexes, polynucleotides, vectors, and/or cells disclosed herein, and/or delivery systems for administering any one of the compositions, complexes, polynucleotides, vectors to a subject in need thereof. Additional aspects relate to methods for inserting a new suppressor tRNA gene into a target site in a genome (e.g., a safe harbor locus site) using prime editing.
The technology described herein provides tissue dissociation well plates, devices, systems, and kits to isolate single-cells or a single-nuclei using wells with roughened, angled bottom surfaces to receive pipette tips delivering tissue samples and isolation buffers. In certain examples, the bottom surfaces of the wells are roughened to aid in breaking down the tissue sample. In other examples, the tip of the pipette is roughened or serrated to aid in breaking down the tissue sample. The wells may be arrayed in a solid rigid upper surface. The pipette tips deliver isolation buffers and/or dissociation fluids to the wells and the tissue samples. The fluid delivery is provided by pumps via one or more perfusion manifolds. A pipette adaptor raises, lowers, and twists the pipette tips. The pipette tips deliver the dissociation fluid, withdraw the tissue samples with a suction force, and return the tissue samples to the well with an expelling force. The pipette tips may be twisted to provide an additional force to break down the tissue sample.
The invention provides for delivery, engineering and optimization of systems, methods and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery systems and tissues or organ which are targeted as sites for delivery. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
wherein:
X is C, N, or —CH—CH—,
Y is Y1 when X is N, and Y is Y1 and Y2 when X is C, or —CH—CH—,
Y1, or Y1 and Y2 independently, are selected from H, hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano or thiol, wherein the lower alkyl or alkoxy is optionally substituted with one or more of hydroxyl, halogen, nitro, amino, cyano, thiol, or a 5- or 6-membered aromatic or non-aromatic ring, optionally substituted with one or more of hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano or thiol, wherein Y1 is not H when X is N; or
Y1 is a 5- or 6-membered aromatic or non-aromatic ring, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxy, or thiol, and Y2 is H, if present; or
Y1 and Y2 together with X form a 5- to 8-membered hydrocarbon ring, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxyl, or thiol;
Z is phenyl, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxyl, or thiol; and
R1 to R4 are each independently H, hydroxyl, halogen, lower alkyl or lower alkoxy;
as well as related pentamidine analogs and their use to inhibit bacterial growth and treat bacterial infection.
C07C 257/18 - Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
A61K 31/40 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
A61K 31/4178 - 1,3-Diazoles not condensed and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/451 - Non-condensed piperidines, e.g. piperocaine having a carbocyclic ring directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
A61K 31/7048 - Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin
C07D 211/34 - Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
C07D 213/78 - Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
C07D 233/64 - Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
C07D 295/155 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
69.
SELF-ASSEMBLING VIRUS-LIKE PARTICLES FOR DELIVERY OF NUCLEIC ACID PROGRAMMABLE FUSION PROTEINS AND METHODS OF MAKING AND USING SAME
The present disclosure provides virus-like particles for delivering gene editing agents such as nucleic acid-programmable DNA-binding proteins (napDNAbps) and base editor fusion proteins (“BE-VLPs” or “eVLPs”), and systems comprising such eVLPs. The present disclosure also provides polynucleotides encoding the eVLPs described herein, which may be useful for producing said eVLPs. Also provided herein are methods for editing the genome of a target cell by introducing the presently described eVLPs into the target cell. The present disclosure also provides fusion proteins that make up a component of the eVLPs described herein, as well as polynucleotides, vectors, cells, and kits.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery systems and tissues or organ which are targeted as sites for delivery. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
C12N 15/01 - Preparation of mutants without inserting foreign genetic material thereinScreening processes therefor
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
C12N 15/63 - Introduction of foreign genetic material using vectorsVectorsUse of hosts thereforRegulation of expression
G06Q 50/00 - Information and communication technology [ICT] specially adapted for implementation of business processes of specific business sectors, e.g. utilities or tourism
H04L 51/52 - User-to-user messaging in packet-switching networks, transmitted according to store-and-forward or real-time protocols, e.g. e-mail for supporting social networking services
H04L 65/1069 - Session establishment or de-establishment
Deep learning tools such as convolutional neural networks (CNNs) and transformers have spurred great advancements in computational biology. However, existing methods are constrained architecturally in context length, computational complexity, and model size. This application introduces a sub-quadratic architecture for modeling, which combines projected gated convolutions and structured state spaces to achieve local and global context with, for example, single-nucleotide resolution. These models outperform CNN-, GPT-, BERT-, and long convolution-based models in many tested genomics tasks without pre-training and with 4×-781× fewer parameters. In the proteomics domain, these models similarly outperform pretrained attention-based models, including ESM-1B and TAPE-BERT, on remote homology prediction without pre-training and while using 3,308×-23,636× fewer parameters.
The present disclosure relates to compositions and methods for combinatorial assessment of nanoscale droplets, as specifically exemplified by massively parallel assessment of spatially-directed (while agnostic as to precise droplet content) combinations of droplets harboring distinct and independently identifiable microbial types and/or chemical compounds or mixtures. More particularly, the disclosure relates to a platform and methodologies for identifying advantageous (including synergistic, additive, etc.) microbial interactions and/or chemical compound or mixture interactions with microbes in a manner that allows for binary, trinary, etc. combinatorial assessments to be performed across a range of many discrete input types of microbes (e.g., 6-16 or more discrete input microbial types), to an extent capable of approaching comprehensive sampling and measurement of microbial community combinations from a selected panel of microbial inputs, optionally also in the presence of chemical compounds or mixtures (e.g., test compounds or mixtures for antimicrobial effect).
The Trustees of Columbia University in the City of New York (USA)
The Broad Institute, Inc. (USA)
President and Fellows of Harvard College (USA)
Inventor
Sternberg, Samuel H.
Gelsinger, Diego
Lampe, George Davis
King Davidson, Rebeca Teresa
Liu, David R.
Miller, Shannon Marie
Witte, Isaac Paterson
Eitzinger, Simon
Berrios Adorno, Kiara N.
Abstract
The present disclosure provides Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated transposon (CRISPR-Tn or CAST) systems, components thereof, and methods for nucleic acid modification using the systems or components. More particularly, the disclosure provides modified Cas proteins and transposon-associated proteins for nucleic acid modification.
The present disclosure relates to a computational framework for detecting localized disruptions in noisy, low-coverage signals. Signature classes may be assigned to detected localized disruptions based on one or more features. A trained model may be applied to classified disruptions in determining associations with target medical conditions.
G16H 50/20 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
75.
SYSTEMS, METHODS, AND COMPOSITIONS FOR TREATING VASCULAR DISEASE
The Board of Trustees of the Leland Stanford Junior University (USA)
The Brigham and Women's Hospital, Inc. (USA)
Inventor
Schnitzler, Gavin Reinhardt
Engreitz, Jesse Michael
Kang, Helen Yihua
Ma, Xueyan Rosa
Gupta, Rajat Mohan
Abstract
Provided herein are methods and compositions for the diagnosis, prognosis, and treatment of a vascular disease, such as coronary artery disease (CAD), in a subject. In particular, provided are methods and compositions for treating a vascular disease in a subject involving administering a therapy to disrupt the cerebral cavernous malformation (CCM) signaling pathway in endothelial cells (e.g., arterial endothelial cells) in the subject. Also provided are methods of determining the likelihood that a subject will respond to a therapy for a vascular disease such as CAD, based on the identification of one or more loss-of-function variants in a CCM pathway associated gene in the subject.
C12N 15/11 - DNA or RNA fragmentsModified forms thereof
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
76.
COMPOSITIONS AND METHODS FOR MODULATING NEURONAL EXCITABILITY
The invention features compositions and methods for treating diseases or disorders associated with undesirable neuronal excitability (e.g., neurodegenerative disease, such as Parkinson's disease or Huntington's disease; or chronic pain, or epilepsy).
Applicants sought to express human iduronate-2-sulfatase (hIDS) in the brain endothelium of a mouse model of Mucopolysaccharidosis type II (MPSII, Hunter's syndrome) to enable enzyme secretion into the brain parenchyma. In this disorder, IDS deficiency results in the pathophysiological accumulation of heparan and dermatan sulfate GAGs. To test the hypothesis, Applicants chose AAV-BI30, an AAV9-derived capsid that has an enhanced in vivo tropism specific to the endothelium in the rodent CNS and can transduce human brain vascular endothelial cells in vitro more efficiently than AAV9. Applicants show that systemic delivery of AAV-BI30: hIDS restored IDS enzyme activity in the brain, liver, and serum of IDS-KO mice (FIG. 1). Importantly, AAV-BI30-mediated gene transfer resulted in the correction of GAG accumulation in the brain (FIG. 2). This effect was not observed when using the AAV-BI30 vector packaging a non-secreting version of hIDS. These findings highlight that targeting endothelial cells throughout the CNS is a promising approach for delivering enzymes across the BBB and restoring lysosomal metabolism.
The disclosure provides for compositions, systems, and methods for long-range targeted mutagenesis. In particular, the disclosure provides engineered compositions comprising a programmable nickase configured to introduce a single-strand nick in double-stranded DNA (dsDNA) at one or more targeted nick sites; a helicase configured to unwind a portion of the dsDNA at the one or more targeted nick sites; and a deaminase configured to introduce one or more base edits within the portion of unwound dsDNA. Also provided are vector and delivery systems comprising one or more polynucleotides encoding the components of the compositions, as well as modified cells, cell populations, animal models, pharmaceutical compositions, and kits comprising the compositions.
Provided herein are compositions, systems, and methods for delivering cargo to a target cell. The compositions, systems, and methods comprise one or more polynucleotides encoding one or more LTR retroelement polypeptides for forming a delivery vesicle and one or more capture moieties for packaging a cargo within the delivery vesicle. The one or more LTR retroelement polypeptides for forming a delivery vesicle may comprise two or more of an LTR retroelement gag protein, a retroelement envelope protein, an LTR retroelement reverse transcriptase, or a combination thereof. The LTR retroelement polypeptide alone, the LTR retroelement envelope protein alone, or both the LTR retroelement-derived polypeptide and LTR retroelement envelope protein may be endogenous. In some embodiments the LTR-retroelement-derived polypeptide is a PNMA polypeptide.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C12N 15/88 - Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using liposome vesicle
Embodiments disclosed herein provide for spatially tagged nuclei that are compatible with any genomic or multiomic single cell/nuclei assay to allow generation of a spatially resolved single cell sequencing library with single cell resolution.
Aspects of the disclosure relate to methods, compositions, and systems for editing a DNA sequence encoding an endogenous tRNA into a suppressor tRNA using base editing (e.g., to treat a disease caused by a premature termination codon or PTC). Additional aspects relate to compositions comprising a gRNA configured to bind to a DNA sequence encoding an endogenous tRNA. Other aspects relate to complexes comprising a base editor and a gRNA that are capable of editing an endogenous tRNA into a suppressor tRNA. In some aspects, the disclosure further relates to polynucleotides encoding one or more nucleic acid sequences encoding the gRNAs, vectors comprising the polynucleotides, and/or cells comprising the polynucleotides, complexes, gRNAs, and/or vectors disclosed herein. Additional aspects further relate to kits comprising any one of the compositions, complexes, gRNAs, polynucleotides, vectors, and/or cells disclosed herein.
The present disclosure provides adenine base editors (ABEs) that have context specificity, i.e., a preference for a pyrimidine positioned 5′ of the target adenosine, or preference for a purine positioned 5′ of the target adenosine. In addition, methods for targeted nucleic acid editing are provided. Further provided are pharmaceutical compositions comprising the ABEs. Also provided are vectors useful for the generation and delivery of the ABEs, including vector systems for engineering the ABEs through directed evolution. Cells containing such vectors and ABEs are also provided. Further provided are methods of treatment and uses comprising administering the ABEs.
Chimeric small molecules comprising an immunogenic display moiety and methods of using the chimeric small molecules to label proteins with the immunogenic display moiety for MHC display on the surface of a cell or to label cell surface proteins with the immunogenic display moiety for display on the surface of a cell, thereby inducing an immune response.
C07K 14/74 - Major histocompatibility complex [MHC]
C07K 16/18 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
C12N 5/078 - Cells from blood or from the immune system
84.
PARTIAL-EMT SIGNATURE FOR PREDICTION OF HIGH-RISK HISTOPATHOLOGIC FEATURES AND CANCER OUTCOMES ACROSS DEMOGRAPHIC POPULATIONS
The present invention advantageously provides for use of a p-EMT signature for the treatment and prognosis of head and neck cancer across demographic groups. The p-EMT signature is differentially expressed across demographic groups. The p-EMT state indicates a high risk of metastasis and adverse clinical features that may be used to direct treatment of head and neck cancer.
C12Q 1/6886 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
G01N 33/574 - ImmunoassayBiospecific binding assayMaterials therefor for cancer
85.
PRIME EDITOR VARIANTS, CONSTRUCTS, AND METHODS FOR ENHANCING PRIME EDITING EFFICIENCY AND PRECISION
The present disclosure provides compositions and methods for prime editing with improved editing efficiency and/or reduced indel formation by inhibiting the DNA mismatch repair path way while conducting prime editing of a target site. Accordingly, the present disclosure provides a method for editing a nucleic acid molecule by prime editing that involves contacting a nucleic acid molecule with a prime editor, a pegRNA, and an inhibitor of the DNA mismatch repair pathway, thereby installing one or more modifications to the nucleic acid molecule at a target site with increased editing efficiency and/or lower indel formation. The present disclosure further provides polynucleotides for editing a DNA target site by prime editing comprising a nucleic acid sequence encoding a napDNAbp, a polymerase, and an inhibitor of the DNA mismatch repair pathway, wherein the napDNAbp and polymerase is capable in the presence of a pegRNA of installing one or more modifications in the DNA target site with increased editing efficiency and/or lower indel formation. The disclosure further provides, vectors, cells, and kits comprising the compositions and polynucleotides of the disclosure. The present disclosure also provides compositions and methods for prime editing with improved editing efficiency and/or reduced indel formation with modified prime editor fusion proteins. The disclosure further provides, vectors, cells, and kits comprising the compositions and polynucleotides of the disclosure.
Compositions and methods for assessing relative macromolecule abundance (for example, RNA expression levels) in a spatially-defined manner across a tissue sample (for example, from brain, lung, liver, kidney, pancreas, and/or heart) are disclosed, specifically providing deep transcriptomic coverage at high-resolution (for example, at approximate 10 μm (single cell) resolution) across multiple locations assessed across the tissue sample
Systems, methods and compositions for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising IsrB polypeptides, novel IsrB nucleases and reprogrammable targeting nucleic acid components and methods and application of use are provided.
Embodiments disclosed herein provide compositions for increasing CCL3 and/or CCL4 interactions with CCR5 and/or CCR1 to enhance an immune response. Applicants identified specific interactions between CD8+ T cells and inflammatory monocytes/macrophages that change during tumor progression from small to medium to large tumors. The ligands CCL3 and CCL4 are expressed in a specific subset of T cells (CD8+ PD-1+ TIM3+ T cells). The receptors CCR5 and CCR1 are expressed in inflammatory monocytes/macrophages. Modulation or maintenance of these interactions can allow enhanced immune responses for treating cancer, as well as for vaccination.
C12Q 1/6809 - Methods for determination or identification of nucleic acids involving differential detection
C12Q 1/6886 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
89.
EVOLVED CYTOSINE DEAMINASES AND METHODS OF EDITING DNA USING SAME
The present disclosure generally relates to evolved cytidine deaminases derived from cytidine deaminases, and methods of editing DNA using the same. In some aspects, the disclosure describes the directed evolution of a TadA-derived adenosine deaminase (TadA-CD) to perform cytidine deamination. In some embodiments, the TadA-CDs comprise a plurality of mutations compared to the parent TadA variant. In some embodiments, the TadA-CD is fused to a programmable DNA binding protein. Other aspects of the disclosure generally relate to a cytosine base editor (CBE) comprising a programmable DNA binding protein and the TadA-CD. In some embodiments, the disclosed cytosine base editor has improved efficiencies of conversion and reduced off-target editing frequencies compared to naturally-occurring CBEs. Also provided are polynucleotides, vectors, and kits useful for the generation and delivery of the CBEs. Cells containing such vectors and CBEs are also provided. Further provided are methods of treatment comprising administering the CBEs.
Artificial intelligence enabled disease profiling is described. An electrocardiogram analysis module is configured to derive disease vectors for a plurality of diseases using electrocardiogram training data from both disease-negative and disease-positive individuals. A standardized input is generated, via a data preprocessor of the electrocardiogram analysis module, from an electrocardiogram recorded from an individual. The standardized input is encoded, by a deep learning autoencoder of the electrocardiogram analysis module, into an embedding, the embedding being a lower-dimensional latent space representation of features extracted from the standardized input. At least one disease risk score for the individual is generated, by a statistical modeling algorithm of the electrocardiogram analysis module, for the plurality of diseases based on the embedding and the disease vectors.
G16H 50/30 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indicesICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for individual health risk assessment
G16H 50/50 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
G16H 50/70 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
91.
GLYCOGEN SYNTHASE KINASE 3 INHIBITORS AND USES THEREOF
The present disclosure provides compounds of Formulae I-A, I-B, II-A, II-B, III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, and VI-B, and compounds shown in Table 13, Table 13A, and Table 14, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, which are GSK3 inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
A61K 31/4375 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring hetero atom, e.g. quinolizines, naphthyridines, berberine, vincamine
A61K 31/438 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring being spiro-condensed with carbocyclic or heterocyclic ring systems
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
A61K 31/4745 - QuinolinesIsoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenanthrolines
A61K 31/496 - Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
A61K 31/497 - Non-condensed pyrazines containing further heterocyclic rings
A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/501 - PyridazinesHydrogenated pyridazines not condensed and containing further heterocyclic rings
A61K 31/5025 - PyridazinesHydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/506 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
A61K 31/519 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
A61K 31/5365 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and at least one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/538 - 1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
A61K 31/5383 - 1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
A61K 31/55 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
C07D 491/22 - Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups , , or in which the condensed system contains four or more hetero rings
C07D 495/22 - Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
Systems, methods and composition for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising novel Fanzor polypeptides and a reprogrammable targeting nucleic acid component and methods and application of use are provided.
The invention provides for systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system.
THE UNITED STATES GOVERNMENT AS REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS (USA)
Inventor
Aragam, Krishna
Huffman, Jennifer
Gaziano, Liam
Abstract
Provided herein are methods and compositions for the diagnosis, prognosis, and treatment of dilated cardiomyopathy (DCM) and heart failure (HF). In particular, provided are methods and compositions for detecting a loss-of-function mutation in the CD36 gene. Provided are methods of determining the likelihood that a subject will respond to a treatment for DCM or HF, based on the identification of a CD36 mutation in a sample from the subject.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
A61K 45/00 - Medicinal preparations containing active ingredients not provided for in groups
G01N 33/68 - Chemical analysis of biological material, e.g. blood, urineTesting involving biospecific ligand binding methodsImmunological testing involving proteins, peptides or amino acids
Disclosed herein are methods and devices for use in early detection of Richter's Syndrome. The methods include sequencing a panel of regions in cell-free DNA molecules and detecting one or more markers that are indicative of Richter's Syndrome.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
G16B 20/20 - Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
G16H 50/20 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
Methods, systems, and compositions comprising genomic encryption are detailed herein. Also provided are methods and applications for authenticating biological material utilizing genomic encryption.
G16B 20/20 - Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
G16B 30/00 - ICT specially adapted for sequence analysis involving nucleotides or amino acids
H04L 9/32 - Arrangements for secret or secure communicationsNetwork security protocols including means for verifying the identity or authority of a user of the system
99.
BIFUNCTIONAL CHIMERIC MOLECULES FOR LABELING OF KINASES WITH TARGET BINDING MOIETIES AND METHODS OF USE THEREOF
The present disclosure relates to chimeric small molecules, which find utility as modifiers of target substrates according to the formula A-L1-E-B or A-L1-E-L2-B, wherein A is a kinase binding moiety; B is a target binding moiety; L1 and L2 are each a linker; and E is an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to targets that are not the natural substrate of the kinase; accordingly, diseases or disorders may be treated or prevented with molecules of the present disclosure.
The present disclosure provides compositions and methods for prime editing with improved editing efficiency and/or reduced indel formation with modified prime editors and prime editor fusion proteins. The disclosure further provides, vectors, cells, and kits comprising the compositions and polynucleotides of the disclosure.
patents
