273results about "Activity regulation" patented technology

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.

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.

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 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.

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 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.

To provide double-stranded nucleic acid complexes with novel structures.SOLUTION: In one embodiment, the present invention relates to a nucleic acid complex comprising a first nucleic acid strand and a second nucleic acid strand, the first nucleic acid strand (1) being capable of hybridizing to at least a part of a target transcript, (2) having an antisense effect on the target transcript, and (3) being a gapmer comprising a central region, as well as 5' and 3' wing regions; the second nucleic acid strand comprising at least one sugar-unmodified central region (first exposed region) consisting of one or two to three consecutive sugar-unmodified ribonucleosides linked by internucleoside linkages that is complementary to a part of the first nucleic acid strand; and the first nucleic acid strand being annealed to the second nucleic acid strand.SELECTED DRAWING: Figure 9

The invention provides recombinant DNA molecules and constructs, as well as their nucleotide sequences, useful for modulating gene expression in plants. The invention also provides transgenic plants, plant cells, plant parts, and seeds comprising the recombinant DNA molecules operably linked to heterologous transcribable DNA molecules, as are methods of their use.

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.

The present disclosure provides double-stranded oligonucleotides, compositions and methods related thereto.The present disclosure encompasses the recognition that the structural elements of double-stranded oligonucleotides, such as base sequence, chemical modifications (e.g., sugar, base and / or internucleotide bond modifications) or patterns thereof, and / or stereochemistry (e.g., backbone chiral center (chiral internucleotide bond) stereochemistry) and / or patterns thereof, can have significant effects on the properties and activities of oligonucleotides, such as RNA interference (RNAi) activity, stability, delivery, etc.The present disclosure also provides methods of treating diseases using the provided double-stranded oligonucleotide compositions, for example, in RNA interference.

A toehold exchange riboregulator gate includes: a gate input toehold domain; a ribosome binding sequence; a start codon; a c spacer domain positioned between the ribosome binding sequence and the start codon; a protein coding sequence; and a self-cleaving ribozyme sequence that produces a double-stranded RNA gate suitable for strand exchange and produces the gate input toehold domain.

Disclosed herein, are hammerhead ribozymes that bind to a target mRNA comprising a NUH ribozyme cleavage site that have enhanced turnover rates. Also described herein, are methods of administering hammerhead ribozymes that bind to a target mRNA comprising a NUH ribozyme cleavage site to treat eye diseases.

To provide high throughput assays for measuring adenovirus replication kinetics.SOLUTION: Recombinant adenovirus genomes containing a heterologous open reading frame (ORF) and a self-cleaving peptide coding sequence are described. The recombinant adenovirus genomes, and recombinant adenoviruses produced by the disclosed genomes can be used, for example, in high- throughput assays to measure virus replication kinetics. Methods for measuring replication kinetics of a recombinant adenovirus are also described. In one aspect, provided are recombinant adenovirus genomes that include a heterologous ORF and a self-cleaving peptide coding sequence, both operably linked to and in the same reading frame as an endogenous adenovirus ORF.SELECTED DRAWING: None

This disclosure relates to a nucleic acid comprising a double stranded RNA molecule comprising sense and antisense strands and further comprising a single stranded DNA molecule covalently linked to at least the 5′ end of either the sense or antisense RNA part of the molecule wherein the double stranded inhibitory RNA targets genes associated with cardiovascular disease in the treatment hypercholesterolemia and diseases associated with hypercholesterolemia such as cardiovascular disease.

The present disclosure provides antisense compounds, methods, and compositions for silencing C9ORF72 transcripts. The present disclosure provides antisense compounds, methods, and compositions for the treatment, prevention, or amelioration of diseases, disorders, and conditions associated with C9ORF72 in a subject in need thereof. Also contemplated are antisense compounds and methods for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with C9ORF72.

To provide modified compositions for use in CRISPR systems and methods of using them.SOLUTION: Described are length-modified and chemically-modified forms of crRNA and tracrRNA for use as reconstituted guide RNAs for interaction with Cas9 of CRISPR systems. The resultant length-modified and chemically-modified forms of crRNA and tracrRNA are economical to produce and can be tailored to have unique properties relevant to their biochemical and biological activity in the context of the CRISPR Cas9 endonuclease system.SELECTED DRAWING: Figure 10

Provided herein are double-stranded nucleic acid inhibitor molecules having a shortened sense strand with a stem loop structure and an antisense strand. Also provided are methods and compositions for reducing target gene expression and methods and compositions for treating a disease of interest.

The present invention relates to a modified siRNA with reduced off-target activity. The siRNA comprises a sense strand and an antisense strand containing a chemical modification represented by formula (I) or a tautomer modification thereof at at least one nucleotide position from positions 2 to 8 in the 5' region of the sense strand. The present invention also relates to a complex, pharmaceutical composition, cell, or reagent kit containing the siRNA, and pharmaceutical uses of the siRNA, the complex, and / or the pharmaceutical composition. The present invention also relates to compounds represented by formula (II) and formula (III) or tautomers thereof, and methods for preparing the same.

The subject invention provides a composition comprising an enomomer which comprises a) a carrier molecule, and b) at least one aptamer, wherein the carrier molecule is an antibody, an antigen-binding moiety, a serum protein, an intracellular protein, a messenger RNA (mRNA) or human serum albumin.

The present invention discloses a novel type of gene silencing technology for modulating target nucleic acid and / or protein levels in cells, tissues, organisms and animals. The new technology provides compositions for use in gene targeting or gene silencing applications, including prevention and treatment of human diseases. The composition comprises an asymmetric, short, duplex RNA molecule where the sense strand is shorter than the antisense strand. The duplex RNA molecule further includes at least one interspersed segment of deoxyribonucleotides monomers. The present invention further provides methods of using the compositions for modulating expression or function of a target gene, or for treatment or prevention of diseases as well as for other medical or biological applications.

The present invention provides, among other things, linear mRNA compositions comprising a poly A tail and a stem loop structure downstream to the poly A tail. Also provided herein are methods of producing mRNA by ligating a stem loop exonuclease blocker using a double-stranded RNA ligase.