The present disclosure relates to methods and compositions for enhanced assessment of exogenous polynucleotide and/or polypeptide-mediated transcriptional perturbations at high throughput and single cell/droplet levels of resolution. In embodiments, nucleic acid fusions of exogenous polynucleotide(s) and associated target transcript(s) are produced within individually sequestered or discretely identifiable cells/lysates and analyzed for exogenous polynucleotide mediated perturbations across a vast population of droplets/cells within individual reactions. Kits for performance of the methods are also provided.
In one aspect, embodiments disclosed herein are directed to engineered CRISPRCas effector proteins that comprise at least one modification compared to an unmodified CRISPR-Cas effector protein that enhances binding of the of the CRISPR complex to the binding site and/or alters editing preference as compared to wild type. In certain example embodiments, the CRISPR-Cas effector protein is a Type II effector protein. In certain other example embodiments, the Type V effector protein is Cas9 or an orthologs or engineered variant thereof. Example Cas9 proteins suitable for use in the embodiments disclosed herein are discussed in further detail below.
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.
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 16/42 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against immunoglobulins (anti-idiotypic antibodies)
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting 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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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.
The disclosure provides methods and compositions for treating blood diseases/disorders, such as sickle cell disease, hemochromatosis, hemophilia, and beta-thalassemia. For example the disclosure provides therapeutic guide RNAs that target the promotor of HBG1/2 to generate point mutations that increase expression of fetal hemoglobin. As another example, the disclosure provides therapeutic guide RNAs that target mutations in HBB, Factor VIII, and HFE to treat sickle cell disease, beta-thalassemia, hemophilia and hemochromatosis. The disclosure also provides fusion proteins comprising a Cas9 (e.g., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA. In some embodiments, the fusion proteins are in complex with nucleic acids, such as guide RNAs (gRNAs), which target the fusion proteins to a DNA sequence (e.g., an HBG1 or HBG2 protmoter sequence, or an HFE, GBB, or F8 gene sequence). Such complexes may be useful for increasing expression of fetal hemoglobin or correcting a poing mutation (e.g., C282Y) in HFE.
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.
The present disclosure provides compounds of Formulae T-A, I-B. II-A. II-B. lll-A, III-B, IV-A. IV-B, V-A, V-B, Vl-A, and VI-B. and compounds shown in Table 13, Table 13 A, 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-crysials, tautomers, stereoisomers, isotopically labeled compounds, or prodrags thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
A61K 31/4745 - Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenanthrolines
9.
COMPOSITIONS AND METHODS RELATED TO BICYCLO[2.2.1] HEPTANAMINE-CONTAINING COMPOUNDS
C07C 211/38 - Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
C07C 205/05 - Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to carbon atoms of rings other than six-membered aromatic rings
C07C 209/34 - Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
C07C 209/40 - Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of hydroxylamino or oxyimino groups
C07C 233/06 - Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
C07C 271/24 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
C07C 311/20 - Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
C07D 209/48 - Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
C07D 333/20 - Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
10.
INHIBITORS OF RNA-GUIDED NUCLEASES AND USES THEREOF
The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in the demand for inhibitory anti-CRISPR molecules. Current small-molecule inhibitor discovery platforms are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity, and require high concentration of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Herein, Applicants report a high-throughput discovery pipeline consisting of a FRET-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentration, and targets all catalytic steps. Applicants applied this pipeline to identify BRD7586, a cell-permeable small-molecule inhibitor of SpCas9, that is 2-fold more potent than current inhibitors. Furthermore, unlike the reported inhibitors, BRD7586 enhanced SpCas9 specificity and its activity was independent of the genomic loci, DNA repair pathway, or mode of nuclease delivery. Overall, these studies describe a general pipeline to identify inhibitors of contemporary and emerging CRISPR-associated nucleases. Described herein are compositions and methods for inhibiting the activity of RNA-guided endonucleases, and methods for identifying such compositions.
A61K 31/4439 - Non-condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
11.
CRISPR-CAS COMPONENT SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION
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 a molecular classifier and a targeted sequencing assay for use in characterization and treatment of diffuse large B-cell lymphoma.
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
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 provides novel cyclic nucleotide derivatives and analogs based on the discovery of novel second messengers generated in human cells in response to challenges to the innate immune system. Compositions find use in modulation of innate immune signaling.
C07H 21/02 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
C07H 21/04 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
A61K 31/712 - Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
A61K 31/7125 - Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
11212 2 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.
C07D 405/14 - Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three 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
HTTFXNFXN genes. Complexes, compositions, and systems comprising a prime editor and any of the pegRNAs disclosed herein are also provided by the present disclosure. The present disclosure further provides polynucleotides, vectors, AAVs, cells, compositions, and kits. Methods of treating Huntington' s disease and Friedreich's ataxia, as well as uses of the compositions, pegRNAs, and systems described herein, are also provided herein.
The present disclosure provides compositions and methods useful in the treatment of trinucleotide repeat disorders, including Huntington's disease and Friedreich's ataxia. The present disclosure also provides gRNAs designed to target the HTT or FXN genes. Complexes comprising a base editor and any of the gRNAs disclosed herein are also provided by the present disclosure. The present disclosure further provides polynucleotides, vectors, cells, compositions, and kits. Methods of treating Huntington's disease and Friedreich's ataxia are also provided herein.
The present invention discloses methods and platforms for generating protein binding proteins with specificity for native peptide-MHC (pMHC) complexes. The pMHC binding proteins can be used in bi-specific antibodies or for generating CAR T cells capable of binding to peptides bound to specific MHC alleles.
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
42 - Scientific, technological and industrial services, research and design
Goods & Services
Scientific research; Scientific laboratory services; Scientific laboratory services in the field of genomics; Research and development services in the field of genomics; Research and development services in the field of genomics, namely, sequencing DNA and RNA; Sample collection and preparation for scientific research purposes
42 - Scientific, technological and industrial services, research and design
Goods & Services
Scientific research; Scientific laboratory services; Scientific laboratory services in the field of genomics; Research and development services in the field of genomics; Research and development services in the field of genomics, namely, sequencing DNA and RNA; Sample collection and preparation for scientific research purposes
09 - Scientific and electric apparatus and instruments
42 - Scientific, technological and industrial services, research and design
Goods & Services
Downloadable genomic and non-genomic datasets for cancer research Providing on-line non-downloadable software for data analysis, perturbational (drug, compound, genetic reagent, biologic) screening results for scientific research purposes, genomic and other omics results for scientific research purposes, and genome-scale pooled genetic perturbation (using RNAi, CRISPR or other genetic means) screening results for scientific research purposes; biomedical research services; biomedical research services in connection with profiling for identifying genes and biomarkers relevant for cancer
09 - Scientific and electric apparatus and instruments
42 - Scientific, technological and industrial services, research and design
Goods & Services
Downloadable genomic and non-genomic datasets for cancer research Providing on-line non-downloadable software for data analysis, perturbational (drug, compound, genetic reagent, biologic) screening results for scientific research purposes, genomic and other omics results for scientific research purposes, and genome-scale pooled genetic perturbation (using RNAi, CRISPR or other genetic means) screening results for scientific research purposes; biomedical research services; biomedical research services in connection with profiling for identifying genes and biomarkers relevant for cancer
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
G16B 40/00 - ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
The subject matter disclosed herein relates using waveform data of a subject to detect one or more diseases or disease etiologies. Particular examples relate to providing a system, a computer-implemented method, and a computer program product to waveform data to detect and differentiate particular diseases and disease etiologies with machine learning models.
G16H 50/20 - ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
G16H 50/30 - ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for individual health risk assessment
G16H 50/70 - ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
Described in certain example embodiments herein are programmable nuclease¬ peptidase compositions, systems, and methods for the manipulation of nucleic acids and/or polypeptides. In some embodiments, the programmable nuclease-peptidase composition comprises a repeat-associated mysterious protein (RAMP) polypeptide; a guide molecule capable of forming a RAMP-guide molecule complex with the RAMP polypeptide and directing sequence specific binding of the complex to a target polynucleotide; and a peptidase capable of binding to the RAMP polypeptide, the guide molecule, or further complexing with the RAMP-guide molecule complex, wherein binding of the RAMP-guide molecule complex to the target polynucleotide initiates binding and/or interaction of the peptidase with a target polypeptide.
Methods and kits are disclosed related to preparing a nucleic acid sample for sequencing that minimizes propagation of false mutations due to amplification of nucleotide damage or alterations confined to one strand wherein at least a portion of the sample is double-stranded.
The present application provides systems, methods and compositions used for targeted gene modification, targeted insertion, perturbation of gene transcripts, nucleic acid editing. Novel nucleic acid targeting systems comprise components of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) systems and transposable elements. Specifically, the disclosure provides an engineered composition comprising: a programmable DNA-binding protein and two or more Tn7-like transposition proteins, wherein at least one of the Tn7-like transposition proteins is connected to the DNA-binding protein or otherwise capable of forming a complex with the DNA-binding protein, wherein the DNA-binding protein comprising a Cas protein including a Cas12k protein, and wherein two or more Tn7-like transposition proteins consisting of TnsB, TnsC, and TniQ.
C12N 15/90 - Stable introduction of foreign DNA into chromosome
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
The subject matter disclosed herein is generally directed to pathogenic Th1 cells whose phenotype is dependent on IL-23R signaling. Th1 cell specific therapeutic targets and gene programs are disclosed herein. In particular, inhibition of CD160 reduces Th1 cell pathogenicity.
The invention features compositions and methods for treating developmental, neurodevelopmental (e.g., Fragile X syndrome (FXS)) or Down syndrome (DS) or neurodegenerative disorders (e.g., Alzheimer's disease (AD)) by increasing expression of Fragile X Mental Retardation Protein (FMRP) in patients having such disorders.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
A61P 25/00 - Drugs for disorders of the nervous system
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered RNA-targeting systems comprising a novel RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.
The present invention includes compounds of formula (I)
The present invention includes compounds of formula (I)
The present invention includes compounds of formula (I)
and methods for its preparation and treatment of disorders with activated peroxisome preoliferator-activated receptor gamma (PPARG), particularly cancer.
C07D 235/18 - Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
C07D 249/20 - Benzotriazoles with aryl radicals directly attached in position 2
C07D 413/04 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07D 413/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
34.
CRISPR EFFECTOR SYSTEM BASED DIAGNOSTICS FOR VIRUS DETECTION
Described herein are compositions and methods of CRISPR effector system mediated detection of targets, including, but not limited to viral targets. Also described herein are devices and kits for carrying out the CRISPR effector system mediated nucleic acid detection assays.
C12Q 1/70 - Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
C12N 15/11 - DNA or RNA fragments; Modified forms thereof
C12Q 1/6806 - Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
G01N 33/543 - Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
35.
FUNCTIONAL GENOMICS USING CRISPR-CAS SYSTEMS FOR SATURATING MUTAGENESIS OF NON-CODING ELEMENTS, COMPOSITIONS, METHODS, LIBRARIES AND APPLICATIONS THEREOF
The application relates to a deep scanning mutagenesis library to interrogate phenotypic changes in a population of cells comprising a plurality of CRISPR-Cas system guide RNAs targeting genomic sequences within at least one continuous genomic region, wherein the guide RNAs target at least 100 genomic sequences upstream of a PAM sequence for every 1000 base pairs within the continuous genomic region and methods for their use.
As described below, the present invention features compositions, panels of biomarkers, and methods for selecting a subject with chronic lymphocytic leukemia (CLL) for treatment using an agent and/or for inclusion in a clinical trial using the agent to treat CLL.
The invention provides for systems, methods, and compositions for altering expression of target gene sequences and related gene products. Provided are stmctural 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 formulation in eukaryotic cells and methods for utilizing the CRISPR-Cas system. In particular the present invention comprehends optimized functional CRISPR-Cas enzyme systems.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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, a 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.
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
C07K 14/005 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
The present invention provides for methods to obtain multiple information-rich samples at different time points from the same cell while minimally disrupting the cell. The subject matter disclosed herein is generally related to nucleic acid constructs for continuous monitoring of live cells. Specifically, the subject matter disclosed herein is directed to nucleic acid constructs that encode a fusion protein and a construct RNA sequence that induce live cells to self-report cellular contents while maintaining cell viability. The present invention may be used to monitor gene expression in single cells while maintaining cell viability.
C12N 15/62 - DNA sequences coding for fusion proteins
C07H 21/04 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
C12Q 1/6897 - Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids involving reporter genes operably linked to promoters
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.
This disclosure provides a method for substantially increasing the concentration of cfDNA in a patient. By injecting a patient with lipid and/or polymer nanoparticles, agents that bind cfDNA, or inhibit deoxyribonucleases prior to collection of a sample of cfDNA, e.g., by way of a liquid biopsy, major pathways for the degradation of cfDNA are temporarily blocked, permitting transient accumulation of cfDNA. This strategy has the potential to dramatically enhance the quality of detection achieved by downstream cfDNA e analytical applications, such as sequencing applications.
The present invention relates to the analysis of complex single cell sequencing libraries. Disclosed are methods for enrichment of library members based on the presence of cell-of origin barcodes to identify and concentrate DNA that is relevant to interesting cells or components that would be expensive or difficult to study otherwise. Also, disclosed are methods of capturing cDNA library molecules by use of CRISPR systems, hybridization or PCR. The present invention allows for identifying the properties of rare cells in single cell RNA-seq data and accurately profile them through clustering approaches. Further information on transcript abundances from subpopulations of single cells can be analyzed at a lower sequencing effort. The methods also allow for linking TCR alpha and beta chains at the single cell level.
C40B 30/04 - Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
C40B 40/06 - Libraries containing nucleotides or polynucleotides, or derivatives thereof
C40B 40/10 - Libraries containing peptides or polypeptides, or derivatives thereof
C40B 50/06 - Biochemical methods, e.g. using enzymes or whole viable microorganisms
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 Methods for making and using and uses of such systems, methods, and compositions and products from such methods and uses are also disclosed and claimed.
The subject matter disclosed herein is generally directed to genetic variants associated with local adiposity traits and metabolic disease. Embodiments disclosed herein provide genetic variants associated with local adiposity traits obtained by adjusting adiposity traits for BMI and height. Embodiments disclosed herein also provide genes linked to variants and associated with the local adiposity traits. The local adiposity traits are associated with metabolic disorders. In example embodiments, variants indicate risk for a metabolic disorder and can be used to determine treatment. In example embodiments, genes associated with local adiposity traits and/or variants can be targeted therapeutically. In example embodiments, a risk for a metabolic disorder can be determined by detecting one or more risk variants associated with a local adiposity trait.
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
A61B 5/00 - Measuring for diagnostic purposes ; Identification of persons
46.
AMYLOID PROTEIN MODIFYING SORTASES AND USES THEREOF
Evolved sortases exhibiting enhanced reaction kinetics and/or altered substrate preferences are provided herein, for example evolved sortases that bind recognitions motifs comprising a LMVGG [SEQ ID NO: 3] sequence. Also provided are methods (e.g., orthogonal transpeptidation and diagnostics methods) for using such sortases.
The invention provides for systems, methods, and compositions for targeting and editing nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a DNA-targeting Cpf1 protein, at least one guide molecule, and at least one adenosine deaminase protein or catalytic domain thereof.
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Aspects of the disclosure relate to Botulinum toxin X (BoNT X) protein variants. The variants provided herein have been evolved to cleave GTP cyclohydrolase 1 (GCH1). Some of the variants provided herein were evolved from a procaspase- 1 cleaving polypeptide. Further aspects of the disclosure relate to nucleic acids encoding the GCH1 cleaving polypeptides described herein and expression vectors comprising the nucleic acids, as well as host cells and fusion proteins comprising the GCH1 cleaving polypeptides described herein, and kits comprising the GCH1 polypeptides, fusion proteins, nucleic acids, expression vectors, or host cells described herein. Further aspects of the disclosure relate to methods of producing BoNT X variants and methods of using the BoNT X protein variants, for example, to reduce pain.
T-type voltage-gated calcium channel potentiators are described herein which are able to augment thalamic function, for example, decrease thalamocortical hyperactivity in patients in need thereof. These potentiators may be useful in many diseases or conditions associated therewith such as schizophrenia and neurodevelopmental disorders. The Cav potentiators typically have the structure of Formula (I) or Formula (V).
A61K 31/166 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon atom of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
A61K 31/407 - 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 condensed with heterocyclic ring systems, e.g. ketorolac, physostigmine
The present disclosure provides a protein which is composed of a sequence including one amino acid sequence among the following (a)-(c) and forms a complex with a guide RNA: (a) an amino acid sequence which includes an amino acid sequence composed of at least amino acid numbers 198-614 in the amino acid sequence represented by SEQ ID NO: 1, and includes a substitution of one or both of E172 and E297; (b) an amino acid sequence in which at least one amino acid is deleted, inserted, substituted, or added in portions other than amino acid numbers 172 and 297 in the amino acid sequence represented by (a); and (c) an amino acid sequence which shares an identity of at least 80% with portions other than amino acid numbers 172 and 297 in the amino acid sequence represented by (a). This protein is a Cas13bt3 variant having improved efficiency and specificity.
The present invention relates to systems, compositions, and methods for altering nucleic acids, such as at a single position (e.g., A/T to G/C or G/C to A/T; in a gene with disease causing SNP). In particular, the present invention relates to engineered CRISPR/Cas systems comprising: a first Cas protein (e.g., Cas5-8 or Cas11) which is optionally tethered or fused to an effector protein selected from: i) an adenine deaminase, ii) a uracil glycosylase inhibitor, or iii) an APOBEC protein; and at least one guide RNA (gRNA) configured to hybridize to a portion of a target nucleic acid sequence. In certain embodiments, the systems further comprise a second Cas protein selected from: i) Cas3, ii) a helicase-deficient Cas3; or iii) a single-strand nicking Cas endonucleases (e.g., Cas9 Nickase H840A Protein).
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
G01N 33/68 - Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
53.
COMPOSITIONS FOR DETECTING SECRETION AND METHODS OF USE
The present invention provides methods and compositions based on a non-naturally occurring nucleic acid construct encoding a fusion protein for quantitating levels of secretion in a single cell which may comprise a protein sequence which may comprise a cytoplasmic domain, a transmembrane domain and a vesicular domain, wherein the vesicular domain may comprise a protein tag sequence, wherein upon expression of the fusion protein by a cell, the fusion protein localizes to the membrane of a secretory vesicle such that the protein tag localizes to the lumen of the secretory vesicle, and wherein the protein tag binds to a cell-impermeable marker; whereby upon secretion of the contents of the secretory vesicle, the protein tag is exposed to the cell-impermeable marker, the fusion protein is recycled back into the cell, and the single cell becomes labeled with the marker relative to the amount of secretion.
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.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
C12N 9/78 - Hydrolases (3.) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
55.
COMPOSITIONS AND METHODS FOR CHARACTERIZING LYMPHOMA AND RELATED CONDITIONS
The invention provides compositions and methods useful in characterizing and/or treating classical Hodgkin's Lymphoma and/or primary mediastinal B-cell lymphoma (PMBL). In embodiments, the characterization is carried out using a biological sample comprising circulating tumor DNA (ctDNA) from a subject.
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
56.
METHODS AND COMPOSITIONS FOR TRANSDUCING HEMATOPOIETIC CELLS
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.
A61K 47/00 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
A61K 47/54 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting 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 disclosure provides a powerful new approach to dual-strand high-throughput next-generation sequencing that improves upon duplex sequencing. The method provides a novel multi-oligonucleotide adapter construct that is ligated to DNA fragments to be sequenced (e.g., genomic DNA fragments) library construction method that concatenates both strands of each DNA duplex into a linear sequence. By physically linking both strands, the products are self-sufficient to form duplex consensus. This strategy has the potential to provide 1,000-fold more accurate sequencing with minimal added cost, and could directly enhance existing products (WGS, WES, targeted panels) offered at the Genomics Platform.
Described herein are pancreatic ductal adenocarcinoma (PDAC) signatures and methods of detecting the same in a sample from heterogeneity-score a subject. Also described herein, are methods of methods of diagnosing, prognosing, and/or treating PDAC in a subject that can include detecting one or more of the PDAC signatures.
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
59.
METHODS FOR IDENTIFYING NOVEL GENE EDITING ELEMENTS
Embodiments disclosed herein provide methods for identifying new CRISPR loci and effectors, as well as different CRISPR loci combinations found in various organisms. Class-II CRISPR systems contain single-gene effectors that have been engineered for transformative biological discovery and biomedical applications. Discovery of additional single-gene or multicomponent CRISPR effectors may enhance existing CRISPR applications, such as precision genome engineering. Comprehensive characterization of CRISPR-loci may identify novel functional roles of CRISPR loci enabling new tools for biomedicine and biological discovery. CRISPR loci have enormous feature complexity, but classification of CRISPR loci has been focused on a small fraction of highly abundant features. Increased genome sequencing has enhanced the sampling of this feature complexity.
G16B 40/00 - ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
G16B 20/00 - ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
G06F 18/2413 - Classification techniques relating to the classification model, e.g. parametric or non-parametric approaches based on distances to training or reference patterns
Described in several embodiments herein are compositions, systems, and methods for targeted gene modification, targeted insertion, perturbation of gene transcripts, and nucleic acid editing. Described in several embodiments are nucleic acid targeting systems that include components of CRISPR systems, VirD polypeptide(s), and DNA polymerase(s).
The present disclosure relates to compositions and methods for detecting nucleic acid sequences (e.g., coding and non-coding RNAs; nuclear/genomic DNA; mtDNA; pathogen nucleic acids, etc.) in a tissue sample, specifically providing improved matrices and matrix-employing methods for performance of nucleic acid capture and amplification in a tissue sample in situ and/or in a manner that retains spatial location information for captured nucleic acids (including nucleic acid-associated macromolecules).
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]pyridin-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
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
The United States of America, as Represented by the Secretary Dept of Health and Human Services (USA)
Inventor
Yamano, Takashi
Nishimasu, Hiroshi
Zetsche, Bernd
Slaymaker, Ian
Li, Yinqing
Fedorova, Iana
Makarova, Kira
Gao, Linyi
Koonin, Eugene
Zhang, Feng
Nureki, Osamu
Abstract
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA or RNA-targeting systems comprising a novel DNA or RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.
G16B 15/00 - ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
G16C 20/30 - Prediction of properties of chemical compounds, compositions or mixtures
G16C 60/00 - Computational materials science, i.e. ICT specially adapted for investigating the physical or chemical properties of materials or phenomena associated with their design, synthesis, processing, characterisation or utilisation
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.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
C12N 15/90 - Stable introduction of foreign DNA into chromosome
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.
Described in several example embodiments herein are engineered programmable pattern recognition compositions and uses thereof. In certain example embodiments, the engineered protein contains an NTPase of a Signal Transduction ATPases with Numerous- associated Domains (STAND) superfamily (STAND NTPase), comprising a pathogen- associated molecular pattern (PAMP) recognition activity, wherein the STAND NTPase and the PAMP recognition activity are derived from the same or different prokaryotes.
Microbes expressing cholesterol oxidoreductase (COR) proteins, methods of engineering the microbes expressing COR proteins, compositions and methods of using the microbes are provided.
A61K 31/575 - Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
A61K 9/00 - Medicinal preparations characterised by special physical form
C12N 15/70 - Vectors or expression systems specially adapted for E. coli
C12N 9/04 - Oxidoreductases (1.), e.g. luciferase acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
C12Q 1/26 - Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
The present disclosure relates to bifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising an enzyme binding moiety, a chemical linker moiety, and a target binding moiety, which may further include an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to proteins that are not the natural substrate of the enzyme. 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 additives; Targeting 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
C07K 1/107 - General processes for the preparation of peptides by chemical modification of precursor peptides
A61K 47/54 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting 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
Described herein are systems, methods, and compositions capable of targeting nucleic acids. Describe in certain exemplary embodiments herein are a class of small Cas proteins (Type II-D Cas proteins) and systems thereof. Also described in certain exemplary embodiments herein are methods of modifying target sequences using the class of small Cas proteins (Type II-D Cas proteins) and systems thereof described herein.
Disclosed herein are methods and systems for correlating continuous physiological processes (e.g., electrophysiological activity) and biomolecular processes (e.g., gene expression) in cells within a tissue. Also disclosed herein are methods for preparing a tissue for continuous electrophysiological recording. Further disclosed herein are systems comprising nanoelectronic devices within cells in a tissue, wherein each nanoelectronic device comprises a unique electronic barcode. The methods and systems described herein comprise any tissue with electrical activity (e.g., brain tissue, heart tissue, nervous system tissue, muscle tissue, pancreas tissue, or gastrointestinal tract tissue). Additionally disclosed herein are methods for disease modeling, methods for discovering a target for treating a disease, and methods for drug screening.
The subject matter disclosed herein is generally directed to methods and compositions for stable transduction of target cells with libraries of genetic elements. The invention reduces intermolecular recombination between library elements and integration of multiple genetic elements.
Embodiments disclosed herein are directed to engineered CRISPR-Cas effector proteins that comprise at least one modification compared to an unmodified CRISPR-Cas effector protein that enhances binding of the CRISPR complex to the binding site and/or alters editing preference as compared to wild type. In certain example embodiments, the CRISPR-Cas effector protein is a Type V effector protein. In certain other example embodiments, the Type V effector protein is Cpf1. Embodiments disclosed herein are directed to viral vectors for delivery of CRISPR-Cas effector proteins, including Cpf1. In certain example embodiments, the vectors are designed so as to allow packaging of the CRISPR-Cas effector protein within a single vector. There is also an increased interest in the design of compact promoters for packing and thus expressing larger transgenes for targeted delivery and tissue-specificity. Thus, in another aspect certain embodiments disclosed herein are directed to delivery vectors, constructs, and methods of delivering larger genes for systemic delivery.
T cell responses are exquisitely antigen-specific and directed against peptide epitopes displayed by human leukocyte antigen (HLA) on the surface of presenting cells. In particular, class II HLA (HLA-II) is remarkably polymorphic, which allows for presentation of diverse peptide antigens to T cells, but also forms the basis for genetic associations with diverse immunopathologies across the spectrum of infectious disease and autoimmunity. Here, Applicants employ monoallelic immunopeptidomics to retrieve over 200,000 unique peptides presented by 41 HLA-II heterodimers covering major alleles across diverse ancestries. Applicants leveraged this expansive dataset to develop computational models that predict peptide antigens based on HLA-II binding properties and infer informative features of the protein antigens from which these peptides derive. Combining both peptide and (contextual) protein features, Applicants develop Context Aware Predictor of T cell Antigens (CAPTAn) to discover novel T cell epitopes from prokaryotes in the human microbiome and the viral pandemic pathogen SARS-CoV-2.
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered RNA-targeting systems comprising a novel RNA-targeting Cas13b effector protein and at least one targeting nucleic acid component like a guide RNA or crRNA.
Engineered or non-naturally occurring systems and compositions comprising novel Cas5- HNH and Cas8-HNH polypeptides are detailed herein. Also provided are methods and applications for the novel Cas5-HNH and Cas8-HNH polypeptides for reprogrammable targeting nucleic acid and polynucleotide components.
C12N 9/16 - Hydrolases (3.) acting on ester bonds (3.1)
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
C12N 15/63 - Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
C12N 15/62 - DNA sequences coding for fusion proteins
C12N 15/66 - General methods for inserting a gene into a vector to form a recombinant vector using cleavage and ligation; Use of non-functional linkers or adaptors, e.g. linkers containing the sequence for a restriction endonuclease
77.
AAV CAPSIDS THAT ENABLE CNS-WIDE GENE DELIVERY THROUGH INTERACTIONS WITH THE TRANSFERRIN RECEPTOR
An engineered AAV capsid is provided, in which at least one protein on the capsid is modified to include a n-mer motif, which promotes transduction of the capsid into the central nervous system (CNS) through interaction with the Transferrin receptor. Further embodiments provide a vector system comprising one or more vectors encoding AAV capsids and a method of delivering cargo to the CNS. The method comprises administering, in vivo or in vitro, a AAV capsid according to embodiments described herein and the AVV capsid comprises one or more cargo molecules.
The present disclosure is directed to methods of screening for pathological mechanisms in neurodevelopmental and neuropsychological disorders using brain organoids. The present disclosure is also directed to methods of screening agents using the brain organoids.
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
G01N 33/50 - Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
79.
THERAPEUTIC TARGETING OF INOSITOL PYROPHOSPHATE SYNTHESIS IN CANCER
The subject matter disclosed herein is generally directed to treating cancers sensitive to phosphate dysregulation with inhibitors of inositol pyrophosphate (PP-InsP) synthesis, in particular, inhibitors of inositol hexakisphosphate kinases IP6Ks.
Described in certain example embodiments herein are engineered delivery vesicle generations systems capable of producing engineered delivery vesicles containing two or more different retroelement polypeptides. Also described herein are methods of making and using the engineered delivery vesicles, such as to deliver one or more cargoes.
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
C12N 15/85 - Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
C12N 15/11 - DNA or RNA fragments; Modified forms thereof
81.
N-[2-({4-[3-(ANILINO)-4-OXO-4,5,6,7-TETRAHYDRO-1H-PYRROLO[3,2-C]PYRIDIN-2-YL]PYRIDIN-3-YL)OXY)ETHYL]PROP-2-ENAMIDE DERIVATIVES AND SIMILAR COMPOUNDS AS EGFR INHIBITORS FOR THE TREATMENT OF CANCER
The present disclosure provides compositions, reagents, and methods for producing capped, circular RNA molecules, circularized RNA molecules, and in particular, circularized mRNA molecules encoding a polypeptide such as a therapeutic protein.
The present invention provides a method of treatment of sarcoma comprising administering to a patient in need thereof a compound of general formula (I),
The present invention provides a method of treatment of sarcoma comprising administering to a patient in need thereof a compound of general formula (I),
The present invention provides a method of treatment of sarcoma comprising administering to a patient in need thereof a compound of general formula (I),
in which R1, R2, R3, and R4, are as defined herein, alone or in pharmaceutical compositions or combinations comprising said compounds as a sole agent or in combination with other active ingredients.
A61K 31/5395 - 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 having two or more nitrogen atoms in the same ring, e.g. oxadiazines
Aspects of the disclosure relate to compositions and methods for targeted protein degradation. In some embodiments, the disclosure relates to methods of evolving protein degrons to interact with certain small molecule inducers (e.g., VS-777, PT- 179, or PK-1016). In some embodiments, the disclosure relates to compositions (e.g., peptides, nucleic acids encoding the protein degrons, etc.) used for targeted protein degradation. In some embodiments, the disclosure relates to methods of degrading a target polypeptide in a cell.
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
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.
Provided herein arc compounds of Formula (I- A), (I-B), or (I-C), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically enriched forms, prodrugs, or mixtures thereof, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases and/or conditions (e.g., neurological disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), metabolic disorder (e.g., obesity, diabetes, X-linked adrenoleukodystrophy (X-ALD)), proliferative disease (e.g., cancers), hepatic disease (e.g., liver cirrhosis), conditions associated with autophagy (e.g., neurodegenerative disease, infection, cancer, conditions associated with aging, heart disease), conditions associated with aging, conditions associated with modulating the mPTP, cardiovascular conditions (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases, or other diseases associated with cyclophilins) in a subject, as well as for reducing oxidative stress. Provided are methods of inhibiting a cyclophilin in a subject, cell, tissue, and/or biological sample. Provided are methods of selectively inhibiting a cyclophilin (e.g., CypD, CypE) in a subject, cell, tissue, and/or biological sample.
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
C07K 7/56 - Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
The present disclosure provides Cas protein variants comprising one or more amino acid substitutions relative to wild-type Casl4al. Fusion proteins comprising the Cas protein variants described herein are also provided by the present disclosure. Further provided herein are methods for modifying a target nucleic acid using the Cas proteins and fusion proteins provided herein. The present disclosure also provides guide RNAs, complexes, polynucleotides, systems, cells, kits, and pharmaceutical compositions.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
C12N 15/63 - Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
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 provided.
C07D 401/06 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
C07F 7/08 - Compounds having one or more C—Si linkages
C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
C07D 405/14 - Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Described and featured are compositions, a system and methods for identifying and selecting substrates of E3 ligases by ubiquitin biotinylation. The components of the compositions, system and methods are ubiquitin- and interaction-specific, thereby providing the enrichment and identification of endogenous or exogenous E3 ligase substrate molecules that are proximally ubiquitinated and biotinylated by components designed to interact both physically and functionally in the compositions, system and methods. The compositions, system and methods are useful and advantageous for identifying and selecting E3 ligase substrates (and/or associated molecules) that are modulated or induced by other agents, such as immunomodulatory imide agents (IMiDs), molecular glues and bifunctional proteolysis targeting chimeras (PROTAC®s).
G01N 33/68 - Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
C12N 9/00 - Enzymes, e.g. ligases (6.); Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating, or purifying enzymes
C12N 15/62 - DNA sequences coding for fusion proteins
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
Systems, methods, and compositions for targeting polynucleotides. More particularly, the disclosure provides non-naturally occurring or engineered DNA or RNA-targeting systems comprising a novel DNA or RNA-targeting nucleic acid-guided nuclease and at least one targeting nucleic acid component like a guide RNA.
Compositions and methods are provided herein for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis. The compositions include fusion proteins comprising nucleic acid programmable DNA binding proteins (napDNAbp) and a polymerase (e.g., reverse transcriptase), which is guided to a specific DNA sequence by a modified guide RNA, named an PEgRNA. The PEgRNA has been altered (relative to a standard guide RNA) to comprise an extended portion that provides a DNA synthesis template sequence which encodes a single strand DNA flap which is synthesized by the polymerase of the fusion protein and which becomes incorporated into the target DNA molecule.
The disclosure features compositions, systems, and methods for preparation and use of efficient RNA nuclear export of ribozyme-assisted circular RNA molecules (racRNAs). In embodiments, the methods involve characterizing a cell or tissue using racRNAs.
C12N 15/11 - DNA or RNA fragments; Modified forms thereof
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
Chimeric, engineered DNA-targeting IscB systems, methods and compositions including novel chimeric IscB polypeptides and reprogrammable targeting nucleic acid components and methods and application of use are provided.
Systems and methods for targeted gene modification, targeted insertion, perturbation of gene transcripts, and nucleic acid editing. The novel nucleic acid targeting systems can comprise components of one or more transposases, one or more components of a CRISPR-Cas system, and a transposable element.
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered RNA-targeting systems comprising a novel RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.
The present disclosure provides zinc finger domain-containing proteins comprising optimized a-, P-, and linker motifs, and fusion proteins comprising said zinc finger domain-containing proteins fused to an effector domain. The present disclosure also provides double-stranded DNA deaminase A (DddA) variants and fusion proteins comprising said DddA variants fused to a programmable DNA binding protein (e.g., any of the zinc finger domain-containing proteins disclosed herein, a TALE protein, or a CRISPR/Cas9 protein). Methods for editing DNA (including genomic DNA and mitochondrial DNA) using the fusion proteins described herein are also provided by the present disclosure. The present disclosure further provides polynucleotides, vectors, cells, kits, and pharmaceutical compositions comprising the zinc finger domain-containing proteins, DddA variants, and fusion proteins described herein.
C07K 14/47 - Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from humans from vertebrates from mammals
99.
CRISPR-CAS COMPONENT SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION
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.
Provided are engineered viral vectors, compositions comprising viral vectors, and methods of producing and using engineered viral vectors. The engineered viral vectors provided herein include capsid proteins derived from densovirus (DNV). Such DNV capsid proteins can assemble in mammalian cells and encapsulate adeno-associated virus (AAV) and/or DNV genomic DNA. The engineered viral vectors may be used as delivery vectors in target gene therapies.
C12N 7/00 - Viruses, e.g. bacteriophages; Compositions thereof; Preparation or purification thereof
C12P 19/34 - Polynucleotides, e.g. nucleic acids, oligoribonucleotides
C07K 16/00 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
C12N 15/11 - DNA or RNA fragments; Modified forms thereof
