424results about "Activity regulation" patented technology

The invention relates to methods of modulating immune cells in a patient by altering microbiota of the patient. The invention also relates to methods of modulating treatments or therapies in a subject organism by altering microbiota of the subject. The invention also relates to cell populations, systems, arrays, cells, RNA, kits and other means for effecting this. In an example, advantageously selective targeting of a particular species in a human gut microbiota using guided nucleic acid modification is carried out to effect the alteration.

Provided herein are nucleic acids useful as guide nucleic acids (gNAs), e.g., guide ribonucleic acids (gRNAs), in a CRISPR system wherein the guide nucleic acids contain one or more modifications to one or more nucleotides, use of such guide nucleic acids in modifying cells, and other uses wherein CRISPR Cas proteins are utilized.

The invention relates to editing oligonucleotides (EONs) that carry stereospecific phosphorothioate internucleotide linkage modifications at specified positions and that do not carry such modifications on positions that would lower RNA editing efficiency. The selection of positions that should or should not carry a phosphorothioate Rp and / or Sp configuration modification is based on computational modelling that revealed incompatibilities of the stereospecific linkages with the intermolecular oxygen-mediated hydrogen bond network.

Disclosed are compositions comprising a nucleic acid molecule. The nucleic acid molecule may encode an exonic sequence or portion thereof of a target ribonucleic acid (RNA) sequence. The nucleic acid molecule may further encode one or more stabilization domains. The one or more stabilization domains may be configured to reduce a cellular nuclease activity compared to a nucleic acid molecule that does not comprise the one or more stabilization domains.

The present invention provides constructs comprising modified riboswitches to regulate expression of a transgene within a subject. Methods of treating a disease, specifically an eye disease, are also contemplated.

Provided herein are self-delivering oligonucleotides that are characterized by efficient RISC entry, minimum immune response and off-target effects, efficient cellular uptake without formulation, and efficient and specific tissue distribution.

The present disclosure provides systems and methods for modulating the occurrence of chromosomal rearrangements, e.g., translocations, in a cell during genome editing. Embodiments are provided for reducing the occurrence of unwanted chromosomal rearrangements, and for increasing the occurrence of desired chromosomal rearrangements.

A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5′ terminal side of the region, (c) one or more nucleotide analogs located on 3′ terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

The invention relates to a modular polypeptide comprising a first partial effector sequence comprising a first part of a circular permutated halotag protein connected to a sensor module sequence, which is connected to a second part of a circular permutated halotag protein. The sensor module is a single polypeptide or a polypeptide pair capable of undergoing conformational change from a first confirmation to a second confirmation depending on the presence or concentration of an analyte compound. The modular peptide is catalytically active in response to an environmental stimulus or in response to the sensor pair interacting.The invention further relates to nucleic acid sequences encoding the modular polypeptide, and to kits comprising same.

Compositions and methods for introducing double-stranded breaks within the SERPINA1 gene are provided. Compositions and methods for reducing and eliminating mutant forms of α1-antitrypsin (AAT), such as seen in subjects having α1-antitrypsin deficiency (AATD), are provided.

The invention relates to an artificial nucleic acid molecule comprising at least one 5′ UTR element which is derived from a TOP gene, at least one open reading frame, and preferably at least one histone stem-loop. Optionally the artificial nucleic acid molecule may further comprise, e.g. a poly(A)sequence, a poyladenylation signal, and / or a 3′ UTR. The invention further relates to the use of such an artificial nucleic acid molecule in gene therapy and / or genetic vaccination.

To provide a metabolically stable phosphorothioate-modified RNA.SOLUTION: The present invention provides a modified oligonucleotide, having a 5' end and a 3' end, and comprising a sense strand and an antisense strand complementary to a target, and at least one modified intersubunit linkage of Formula I, where at least one modified oligonucleotide is incorporated into the antisense strand or sense strand of an siRNA.SELECTED DRAWING: None

Provided herein are nucleic acids useful as guide nucleic acids (gNAs), e.g., guide ribonucleic acids (gRNAs), in a CRISPR system wherein the guide nucleic acids contain one or more modifications to one or more nucleotides, use of such guide nucleic acids in modifying cells, and other uses wherein CRISPR Cas proteins are utilized.

One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. Other aspects of the invention relate to pharmaceutical compositions comprising these dsRNA molecules suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA molecules, e.g., for the treatment of various disease conditions.

This invention provides guide RNA (gRNA) constructs designed to enhance safety and precision in therapeutic gene editing across RNA-guided systems. The constructs incorporate a non-nucleotide linker near the middle of the spacer sequence, reducing truncated spacer impurities (e.g., n−1 variants) during production by ligating short RNA segments (e.g., 10 nt and 22 nt)—minimizing off-target risks in gene editing therapies. Additionally, a DNA restriction enzyme cleavage site near the spacer's internal end enables excision of a short RNA fragment (e.g., 32 nt for spCas9) for precise spacer purity analysis via LC-MS or electrophoresis. These features ensure robust GMP production and quality control, overcoming limitations of conventional gRNAs and long RNAs (>160 nt) used in diverse editing platforms. Applicable to CRISPR-based and other RNA-guided methods, the constructs maintain or enhance activity, offering a scalable, safe solution for therapeutic gene editing.

Oligomeric compounds (including those that are antisense agents or portions thereof) are provided that comprise a modified oligonucleotide having at least one modified internucleoside linking group.SOLUTION: By an oligomeric compound comprising a modified oligonucleotide consisting of 12 to 70 linked nucleosides linked via internucleoside linking groups, wherein at least one nucleoside comprises a modified sugar moiety and wherein at least one internucleoside linking group is a phosphodiester or phosphorothioate internucleoside linking group.SELECTED DRAWING: Figure 1

To provide a nucleoside derivative or a salt thereof, which can yield an oligonucleotide derivative or a salt thereof with high thermal stability when used as a component of a double-stranded nucleic acid such as double-stranded RNA.SOLUTION: Provided is a nucleoside derivative represented by formula (1), or a salt thereof. In the formula, R1 represents an alkoxy group, a hydrogen atom, or a halogen atom; R2 and R4 may be the same or different and each represent a hydrogen atom, a protecting group for a hydroxyl group, a phosphate group, a protected phosphate group, or -P(=O)nR5R6; R3 represents -(CH2)mNHR7; and B represents a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.SELECTED DRAWING: None

To provide dsRNA molecules which are advantageous for inhibition of target gene expression while having reduced off-target gene silencing effects.SOLUTION: The present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The antisense strand of the dsRNA molecule comprises at least one thermally destabilizing nucleotide occurring at a seed region; the dsRNA comprises at least four 2'-fluoro modifications; and the sense strand of the dsRNA molecule comprises a ligand, where the ligand is an ASGPR ligand.SELECTED DRAWING: None

The present disclosure relates generally to (CRISPR) RNA (crRNA) for the precision silencing of transcripts. In some embodiments, the crRNA are enriched for guanosine (G) nucleotides at key spacer positions, which is useful in enhancing the silencing efficacy of otherwise inefficient crRNA, thereby expanding the targeting spectrum of Cas13 endonucleases, e.g., Cas13b and Cas13d. In other embodiments, the crRNA comprise a spacer sequence having at least one nucleotide mismatch relative to the target RNA sequence, wherein the target RNA sequence is a wild-type transcript and / or a variant transcript (e.g., a transcript comprising a single nucleotide variant (SNV)). The present disclosure also provides RNA editing systems comprising the crRNA described herein in complex a Cas13 effector protein and a target RNA sequence, methods for the selective targeting of transcripts encoding proteins that are difficult to target, or are not amenable to pharmacological targeting, e.g., oncogenic fusion transcripts or oncogenic transcripts comprising single nucleotide variant(s), and methods for the design and selection of potent crRNA.

Some aspects of the present disclosure provide compositions, methods, systems, and kits for modulating the activity and / or improving the specificity of RNA-programmable endonucleases such as Cas9. [Solution] For example, provided herein are guide RNAs (gRNAs) that can be engineered to exist in an "on" or "off" state and regulate the binding and thus cleavage activity of an RNA-programmable endonuclease. Some aspects of the present disclosure provide gRNAs that sense mRNAs that modulate the activity of an RNA-programmable endonuclease based on the presence or absence of a target mRNA. Some aspects of the present disclosure provide gRNAs that modulate the activity of an RNA-programmable endonuclease based on the presence or absence of extended DNA (xDNA).

To reduce the strong hepatotoxicity of antisense nucleic acids that incorporate an artificial nucleobase (e.g., LNA).SOLUTION: The present invention provides a bridged antisense nucleic acid for which antisense nucleic acid-induced toxicity is reduced by the supplemental addition to the wing region of a specific artificial nucleobase (e.g., MCA), while retaining the sequence of the antisense nucleic acid and the number of artificial nucleobases (e.g., LNA). The present invention also provides an antisense nucleic acid drug having a remarkably-reduced hepatotoxicity.SELECTED DRAWING: None

Disclosed herein is a high Tm RNA nanostructure that can be composed of one or more modules or motifs for constructing a hierarchical or non-hierarchical RNA nanostructure. The RNA nanostructure can have a core domain and three or more double-stranded arms and formulations thereof to conjugate a large amount of therapeutic agents, pH-responsive or enzyme-cleavable drug cargoes. Also disclosed herein is a design strategy for generating synthetic RNA oligonucleotides that can self-assemble into highly thermostable RNA structures. Also disclosed herein is the use of the RNA nanostructure described herein.

The disclosure provides novel methods and compositions for gene editing. In particular, the disclosure relates to compositions and methods of making modified nucleic acid donor templates for highly efficient and precise gene editing.

Some aspects of this disclosure provide compositions, methods, systems, and kits for controlling the activity and / or improving the specificity of RNA-programmable endonucleases, such as Cas9. For example, provided are guide RNAs (gRNAs) that are engineered to exist in an “on” or “off” state, which control the binding and hence cleavage activity of RNA-programmable endonucleases. Some aspects of this disclosure provide mRNA-sensing gRNAs that modulate the activity of RNA-programmable endonucleases based on the presence or absence of a target mRNA. Some aspects of this disclosure provide gRNAs that modulate the activity of an RNA-programmable endonuclease based on the presence or absence of an extended DNA (xDNA).

Disclosed herein are compositions comprising an oligonucleotide that inhibits the expression of MST1. The oligonucleotide includes a small interfering RNA (siRNA), as well as these compositions for use in methods of treating lung disorders

To provide compounds, compositions and methods for modulating the expression of human GST-π using RNA interference.SOLUTION: The RNA interference molecules can be used in methods for preventing or treating diseases such as malignant tumors. Provided are a range of siRNA structures, comprising one or more nucleotides being modified or chemically-modified. Advantageous structures include siRNAs with 2'-deoxy nucleotides located in the seed region, as well as other nucleotide modifications.SELECTED DRAWING: Figure 1

To provide a C9orf72 oligonucleotide, a composition, and a method for treatment of C9orf72-associated conditions, disorders, or diseases including amyotrophic lateral sclerosis and frontotemporal dementia.SOLUTION: Provided is an oligonucleotide comprising at least one modification of a sugar, a base, or an internucleotidic linkage, wherein the base sequence of the oligonucleotide is or comprises at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 contiguous bases of a base sequence that is at least 80% identical with or complementary to a base sequence of a C9orf72 gene or a transcript thereof, and wherein a nucleobase at a 3' end of the oligonucleotide is optionally replaced by a replacement nucleobase selected from I, A, T, U, G, and C.SELECTED DRAWING: None

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.