2949 results about "Oligonucleotide" patented technology

Disclosed herein are methods of amplifying an analyte in a biological sample using a bridging oligonucleotide that hybridizes to a captured analyte. The methods disclosed herein include steps of (a) contacting a biological sample with a substrate having capture probes comprising a capture domain and a spatial barcode; (b) hybridizing the analyte to the capture domain; and (c) contacting the analyte to a bridging oligonucleotide comprising (i) a capture-probe-binding sequence, and (ii) an analyte-binding sequence; (d) extending the bridging oligonucleotide; and (e) determining (i) all or a part of the sequence of the analyte, or a complement thereof, and (ii) the spatial barcode, or a complement thereof, and using the determined sequence of (i) and (ii) to determine the location of the analyte in the biological sample.

The present disclosure features methods, compositions, and kits for spatially barcoded, reusable master oligonucleotide probes.

Aspects of the disclosure relate to oligonucleotides designed to target DUX4 RNAs and targeting complexes for delivering the oligonucleotides to cells (e.g., muscle cells) and uses thereof, particularly uses relating to treatment of disease (e.g., FSHD). Wherein a complex comprises an anti-transferrin receptor 1 (TfR1) antibody covalently linked to an oligonucleotide configured for reducing expression or activity of DUX4.

Provided herein are methods identifying protein-protein interactions in a single cell context. In some cases, the methods may be used to measure the abundance of protein-protein interactions in a single cell context. In some cases, the methods may be used to map relationships (e.g., spatial relationships) between proteins in a single cell context. Generally, the methods employ the use of proximity probes coupled with splint oligonucleotides to link information about the relationship of proteins within a single cell context, which may then be read in a downstream process (e.g., a sequencing reaction).

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of DUX4. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Provided herein are method for determining a location of nucleic acids in fixed biological samples, in which the method includes use of a template switching oligonucleotide (TSO) and a randomer during second strand synthesis.

This disclosure relates to methods for spatial profiling of analytes present in a biological sample. Also provided are methods for using spatially barcoded substrates to detect a biological analyte in a cell culture, an organism, and organoid. Also provided are methods for using spatially barcoded substrates to detect the temporal profile of a biological analyte.

Among other things, the present disclosure provides various technologies including chirally controlled oligonucleotide compositions and technologies tor manufacturing and using such oligonucleotide compositions. In some embodiments, the present disclosure provides technologies useful for allele -specific knockdown of mutant Huntingtin transcripts. In some embodiments, tire present disclosure provides technologies useful for reducing the expression, level, amount, and / or activity of mutant Huntingtin transcripts or products thereof. In some embodiments, the present disclosure provides methods for treating Huntington's disease.

Among other things, the present disclosure provides USH2A oligonucleotides, and compositions and methods of use thereof, for preventing and / or treating various conditions, disorders or diseases. In some embodiments, provided USH2A oligonucleotides comprise nucleobase modifications, sugar modifications, internucleotidic linkage modifications and / or patterns thereof, and have improved properties, activities and / or selectivities. In some embodiments, the present disclosure provides USH2A oligonucleotides, compositions and methods for preventing and / or treating USH2A-related conditions, disorders or diseases, such as Usher Syndrome (e.g., Usher Syndrome Type 2A), atypical Usher syndrome, or nonsyndromic retinitis pigmentosa.

Disclosed herein are methods of amplifying an analyte in a biological sample using a bridging oligonucleotide that hybridizes to a captured analyte. The methods disclosed herein include steps of (a) contacting a biological sample with a substrate having capture probes comprising a capture domain and a spatial barcode; (b) hybridizing the analyte to the capture domain; and (c) contacting the analyte to a bridging oligonucleotide comprising (i) a capture-probe-binding sequence, and (ii) an analyte-binding sequence; (d) extending the bridging oligonucleotide; and (e) determining (i) all or a part of the sequence of the analyte, or a complement thereof, and (ii) the spatial barcode, or a complement thereof, and using the determined sequence of (i) and (ii) to determine the location of the analyte in the biological sample.

Among other things, the present disclosure provides oligonucleotides, compositions, and methods thereof. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and / or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and / or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and / or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., knockdown ability, stability, delivery, etc. In some embodiments, the oligonucleotides decrease the expression, activity and / or level of a C9orf72 gene, including but not limited to, one comprising a repeat expansion, or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in treatment of C9orf72-related disorders.

Aspects of the disclosure relate to methods of reducing fatigue in a subject having myotonic dystrophy type 1 (DM1). Aspects of the disclosure relate to methods of treating one or more symptoms assessable by the MDHI (e.g., a GI symptom, myotonia, upper extremity function impairment, fatigue, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment) in a subject having myotonic dystrophy type 1 (DM1). In some embodiments, the methods comprise administering to the subject a composition comprising complexes (e.g., muscle targeting complexes) comprising an oligonucleotide (e.g., a DMPK- targeting oligonucleotide) covalently linked to an antibody (e.g., anti-TfRl antibody).

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Aspects of the disclosure relate to compositions comprising a plurality of complexes comprising an antibody (e.g., anti-TfRI antibody) covalently linked to one or more oligonucleotides (e.g. a DMPK targeting oligonucleotide), each oligonucleotide being covalently linked at a linkage site represented by a lysine (K) residue of the antibody. In some embodiments, the antibody comprises a heavy chain comprising a heavy chain variable region (VH) and a heavy chain constant region, and a light chain comprising a light chain variable region (VL) and a light chain constant region, wherein at least 80% (e.g., 80%-98%, 80%-95%, 80%-90%, 85%-98%, 85%-95%, 85%-90%, 90%-98%, 90%-95%, 95%-97%, or more) of the light chain constant regions of the antibodies of the complexes in the composition are independently covalently linked to an oligonucleotide at a linkage site represented by K188 (based on Kabat numbering) and / or a linkage site represented by K190 (based on Kabat numbering) of the light chain constant regions of the antibodies.

Aspects of the disclosure relate to methods of reducing expression or activity of DMPK (e.g., reducing the level of a mutant or wild-type DMPK RNA, or the activity of a DMPK gene product) and / or methods of treating myotonic dystrophy (e.g., DM1) in a subject. In some embodiments, the methods comprise administering to the subject a composition comprising complexes (e.g., muscle targeting complexes) comprising an oligonucleotide (e.g., a DMPK—targeting oligonucleotide) covalently linked to an antibody (e.g., anti-TfR1 antibody).

The invention is directed to methods and systems for producing a surface coated with a plurality of spatial barcodes. In one aspect, beads carrying barcode oligonucleotides are disposed on a surface after which hydrogel chambers are synthesized around each bead and barcode oligonucleotides are released to be captured on the surface in the interiors of the chambers. Captured oligonucleotide barcodes are amplified and optionally sequenced to form a coating of spatial barcodes.

A modification template for improving the inhibitory effect of a double-stranded oligonucleotide on a target gene, a combination thereof and the use thereof. The double-stranded oligonucleotide is an siRNA and contains a sense strand and an antisense strand, and each nucleotide of the sense strand and antisense strand is a modified nucleotide. The double-stranded oligonucleotide is modified with a special modification template, and has a significantly improved inhibition rate on a target gene compared with a basic sequence.

To provide a method for detecting the presence of multiple specific nucleic acid sequences or single nucleotide polymorphisms in a temperature-dependent fashion.SOLUTION: Provided is a method, in which an invasive oligonucleotide and a primary probe oligo (a 5' flap oligonucleotide) hybridize to a target strand nucleic acid to form an invasive cleavage structure cleavable by a FEN-1 endonuclease to release a cleaved 5' flap (primary cleaved flap); in a secondary reaction, the primary cleaved flap from the primary reaction hybridizes to a FRET cassette 1, a hairpin oligonucleotide labeled with a fluorescent dye and a quencher molecule, to form a second invasive cleavage structure that is cleavable by a FEN-1 endonuclease at a site between the fluorophore and a quencher; and cleavage of FRET cassette 1 separates the quencher from the fluorophore, such that fluorescence signal from the fluorophore can be detected.SELECTED DRAWING: Figure 1

A method of making a barcoded surface includes synthesizing a plurality of arrays arranged in rows and columns. Each array can include a plurality of discrete reaction sites with a first oligonucleotide containing a first unique array barcode sequence. The first unique array barcode sequences of the first oligonucleotides corresponds to a mapped discrete reaction site location within the array. A second oligonucleotide can be coupled to the first oligonucleotide that contains a second unique barcode sequence. The first unique barcode sequences of the second oligonucleotides corresponds to a mapped first sub-group location within the plurality of arrays.

Provided are a double-stranded oligonucleotide agent and uses. The double-stranded oligonucleotide agent comprises a specific cleavage site for an endonuclease, wherein the cleaved double-stranded oligonucleotide agent is capable of inhibiting expression of the target gene via RNA interference (RNAi).

Among other things, the present disclosure provides designed DMD oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for repairing mutant DMD transcripts by skipping exon 51 or exon 53, so that the transcript can be translated into an internally truncated but at least partially functional Dystrophin protein variant. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD) DMD transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as muscular dystrophy, including but not limited to Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.

Among other things, the present disclosure provides oligonucleotide compositions and methods thereof. In some embodiments, oligonucleotides comprise various chemical modifications. In some embodiments, the present disclosure provides technologies useful for manufacturing oligonucleotides.

The present invention discloses a pharmaceutical composition comprising a circular RNA and a drug delivery carrier. Compared with traditional linear 1 * siRNA and annular 1 * siRNA, the number of repeated series connection of positive-sense strands is increased to include but not limited to two or more, it is accidentally found that the silence effect is remarkably enhanced, the expression level of the PCSK9 gene can be remarkably reduced, and degradation of mRNA of PCSK9 protein is mediated. The nano-particles are used for delivering oligonucleotide, so that the stability is improved, the immunogenicity is reduced, the effects of lowering cholesterol, reducing aortic plaque load and resisting atherosclerosis are improved, and the nano-particles are safe and free of obvious liver and kidney toxicity and have a wide application prospect in the aspect of preparing medicines for treating hypercholesterolemia and coronary heart disease.

Among other things, the present disclosure provides oligonucleotides, compositions and methods thereof that can bring about specific editing of a target adenosine in a target RNA molecule. Such oligonucleotides, compositions and methods are useful to treat, prevent, or ameliorate MECP2 associated disorders, diseases and syndromes that can benefit from adenosine modification.

The present disclosure provides compositions, methods, systems, and devices for polynucleotide processing and analyte characterization. Such polynucleotide processing may be useful for a variety of applications, including analyte characterization by polynucleotide sequencing. The compositions, methods, systems, and devices disclosed herein generally describe barcoded oligonucleotides, which can be bound to a bead, such as a gel bead, useful for characterizing one or more analytes including, for example, protein (e.g., cell surface or intracellular proteins), genomic DNA, and RNA (e.g., mRNA or CRISPR guide RNAs). Also described herein, are barcoded labelling agents and oligonucleotide molecules useful for “tagging” analytes for characterization.

The invention belongs to the field of biological medicines, and particularly relates to a modified double-stranded oligonucleotide, and a conjugate and a composition thereof. The double-stranded oligonucleotide provided by the invention effectively enhances the activity of the double-stranded oligonucleotide for inhibiting the expression of the target gene by performing specific modification on the nucleotide at a specific site, can efficiently inhibit the expression of the target gene in both in-vitro and in-vivo experiments, and surprisingly, the double-stranded oligonucleotide provided by the invention has a good application prospect. The modification on the double-stranded oligonucleotide can be generally used for siRNA designed for various different target genes, and the inhibition rate of the siRNA on the target genes can be effectively improved.

The present disclosure features useful oligonucleotide compositions and methods related thereto. The present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g. modifications of sugar, base and / or internucleotide linkages) or patterns thereof, can have a significant impact on oligonucleotide properties and activities. The present disclosure also provides methods to treat disorders for which deamination of an adenosine in an mRNA produces a therapeutic result, e.g., in a subject in need thereof.

Among other things, the present disclosure provides various technologies including chirally controlled oligonucleotide compositions and technologies for manufacturing and using such oligonucleotide compositions. In some embodiments, the present disclosure provides technologies useful for preventing or treating various conditions, disorders or diseases, e.g., Duchenne Muscular Dystrophy.