1229results about "Splicing alteration" patented technology

Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes (e.g., wherein each complex is of the exemplary formula shown below) comprising a phosphorodiamidate morpholino oligomer (e.g., useful for targeting DMD) covalently linked to an antibody (e.g., anti-TfR1 antibody). In some embodiments, the complexes are formulated with histidine (e.g., L-histidine) and sucrose at a specified pH (e.g., about 5.0 to 7.0). Also provided are uses of these formulations for treating a subject having a mutated DMD allele associated with Duchenne Muscular Dystrophy.

Aspects of the disclosure relate to methods of promoting expression or activity of a dystrophin protein and / or methods of treating DMD in a subject. In some embodiments, the methods comprise administering to the subject a composition comprising complexes (e.g., muscle targeting complexes) comprising a phosphorodiamidate morpholino oligomer (e.g., useful for targeting DMD) covalently linked to an antibody (e.g., anti-TfR1 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 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.

To provide constructs, vectors, relative host cells and pharmaceutical compositions which allow an effective gene therapy, in particular of genes larger than 5Kb.SOLUTION: The present invention implements cellular large protein reconstitution by providing to a target cell two or more fragments of large protein fused to split inteins to promote intein-mediated trans-splicing and reconstitute the functional protein.SELECTED DRAWING: None

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.

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 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).

Among other things, the present disclosure provides oligonucleotide compositions and methods thereof. In some embodiments, oligonucleotides comprise various chemical modifications of sugars, nucleobases, and / or internucleotidic linkages and patterns thereof and are useful for exon skipping. In some embodiments, the present disclosure provides technologies useful for skipping exon 52 of dystrophin (DMD) transcripts. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, the present disclosure provides methods for preventing or treating conditions, disorders or diseases including Duchenne muscular dystrophy.

Among other things, the present disclosure provides oligonucleotide compositions and methods thereof. In some embodiments, oligonucleotides comprise various chemical modifications of sugars, nucleobases, and / or internucleotidic linkages and patterns thereof and are useful for exon skipping. In some embodiments, the present disclosure provides technologies useful for skipping exon 44 of dystrophin (DMD) transcripts. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, the present disclosure provides methods for preventing or treating conditions, disorders or diseases including Duchenne muscular dystrophy.

Among other things, the present disclosure provides oligonucleotide compositions and methods thereof. In some embodiments, oligonucleotides comprise various chemical modifications of sugars, nucleobases, and / or intemucleotidic linkages and patterns thereof and are useful for exon skipping. In some embodiments, the present disclosure provides technologies useful for skipping exon 45 of dystrophin (DMD) transcripts. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, the present disclosure provides methods for preventing or treating conditions, disorders or diseases including Duchemie muscular dystrophy.

Among other things, the present disclosure provides oligonucleotide compositions and methods thereof. In some embodiments, the present disclosure provides technologies useful for exon skipping in cell populations, e.g., myocyte stem cells. In some embodiments, the present disclosure provides technologies useful for restoring functioning of myocyte stem cells. In some embodiments, the present disclosure provides technologies useful for regeneration of myocyte stem cells. In some embodiments, the present disclosure provides technologies useful for differentiation of myocyte stem cells. In some embodiments, the present disclosure provides methods for preventing or treating conditions, disorders, or diseases including Duchenne muscular dystrophy.

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.

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.

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.

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.

Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes comprising an oligonucleotide (e.g., useful for targeting DMPK) covalently linked to an antibody (e.g., anti-TfR1 antibody).

Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes comprising an oligonucleotide (e.g., useful for targeting DMPK) covalently linked to an antibody (e.g., anti-TfR1 antibody).

Disclosed herein are therapeutic applications of CRISPR / Cpf1-based genome editing.

The present disclosure provides compositions and methods of use thereof for targeting trans- splicing of a pre-mRNA in a cell utilizing small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs), and related methods.

Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.

Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.

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.

Disclosed herein are antibody oligonucleotide conjugates and pharmaceutical compositions that induce an alteration in an incorrectly spliced dystrophin mRNA transcript to induce exon 44 skipping. Also described herein include methods for treating muscle dystrophy including Duchenne muscular dystrophy that comprises administering antibody oligonucleotide conjugates or a pharmaceutical composition that induces alteration in an incorrectly spliced dystrophin mRNA transcript to induce exon 44 skipping.

Disclosed are methods of treating a subject with a neurological disease associated with a splicing defect caused by TDP-43 proteinopathies, comprising administering to said subject an agent to increase expression levels and / or stability of hnRNP L, thereby attenuating and / or repairing the splicing defect. The disclosure also relates to nucleic acids targeting heterogeneous nuclear ribonucleoprotein L (hnRNP L), and their use.

Agents that target a processed mRNA, e.g., the 5′ UTR of the processed mRNA, can modulate protein expression, e.g., via modulation of translation of the processed mRNA. Alternative splicing events in genes can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression. Agents that target the alternative splicing events in genes can modulate the expression level of proteins. Therapeutic agents, which can modulate protein expression by targeting a processed mRNA and / or alternative splicing events, can promote functional protein expression in patients and / or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition or disease associated with protein deficiency and / or mitochondrial function deficit.

Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes comprising an oligonucleotide (e.g., useful for targeting DMPK) covalently linked to an antibody (e.g., anti-TfR1 antibody).

Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.

Disclosed herein are UNC13A oligonucleotides with one or more spacers or without a spacer. In various embodiments, UNC13A oligonucleotides with spacer(s) reduce mis-spliced UNC13A transcripts and increase full length UNC13A transcripts, thereby imparting therapeutic efficacy against neurological diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or Alzheimer's disease (AD).