81 results about "Myotonic dystrophy gene" patented technology

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 a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

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 a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

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 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 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 a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

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 present disclosure provides methods, uses, kits, and compositions comprising a compound of Formula (I), and either a second compound of Formula (I) or a compound of Formula (II). In one aspect, the methods are for treating a neurological disease associated with repeat expansions and / or RAN protein accumulation, reducing the level of one or more repeat associated non-AUG (RAN) proteins, and reducing the accumulation of RAN proteins in a subject and / or biological sample. Exemplary diseases associated with repeat expansions include, but are not limited to, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, myotonic dystrophy type 1, myotonic dystrophy type 2, spinocerebellar ataxia, Alzheimer's disease, Huntington's disease, Fragile X Tremor Ataxia Syndrome, and Fragile XE syndrome.

The disclosure relates to compositions and methods for modulating, e.g., reducing or eliminating, the expression of mutated DMPK via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects who have, have been diagnosed with having, or are at risk of having myotonic dystrophy type 1 or another DMPK-related disorder.

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).

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 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 a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

The disclosure relates to compositions and methods for modulating, e.g., reducing or eliminating, the expression of mutated DMPK via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, suspected of having, or having myotonic dystrophy type 1 or another DMPK-related disorder or at least one symptom thereof.

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle atrophy or myotonic dystrophy.

The present invention relates to the use of TDP1 and eltrombopag in the treatment of myotonic dystrophy type 2. The present invention uses a fruit fly model to identify that TDP1 knockdown can effectively rescue neurodegeneration in the CCTG repeat fruit fly model, reduce pigment production block, cell death and ommatidium fusion, and improve motor defects. At the same time, in vitro screening using small molecules found that eltrombopag can be used as a TDP1 inhibitor and can significantly reduce disease cytotoxicity. The present invention provides a new target and pharmacological substance for CCTG repeat expansion diseases in myotonic dystrophy type 2, and expands the medical use of eltrombopag. The present invention provides a new drug with clinical application prospects for the treatment of CCTG repeat expansion diseases in myotonic dystrophy type 2.

Myotonic Dystrophy type 1 (DM1) is an inherited disease characterized by multi-systemic symptoms, particularly in skeletal muscles (progressive weakness and atrophy, myotonia). The inventors screened 7 500 bioactive compounds for their ability to improve the myogenic fusion and reduce the molecular hallmarks of DM1 skeletal muscle cells. The inventors found that five compounds, all inhibiting HDAC6, a cytoplasmic histone deacetylase, were effective at the micromolar range in normalizing the myogenic fusion, reducing the number of nuclear foci of mutant DMPK mRNA, decreasing the expression level of DMPK mRNA, restoring the splicing of several genes, and increasing the acetylation of SMAD3, a transcription factor involved in muscle development. The effects of HDAC6 inhibitors were observed both in immortalized and hiPSC-derived skeletal muscle cells from DM1 patients, and in different stages of differentiation. Thus, the present invention relates to the use of selective HDAC6 inhibitors for the treatment of DM1.

The disclosure relates to double stranded ribonucleic acid (dsRNA) agents and compositions targeting a dystrophy myotonic protein kinase (DMPK) gene, as well as methods of inhibiting expression of a DMPK gene and methods of treating subjects having a DMPK-associated disease or disorder, e.g., myotonic dystrophy (DM), using such dsRNA agents and compositions.

The invention discloses an inhibitor acting on a TDP1 target spot and application of the inhibitor. The active ingredient of the inhibitor comprises Lawsone (2-hydroxy-1, 4-naphthoquinone) or SPI-112 (Sodium Sulfonate I-112). The Lawsone is a naphthoquinone compound with oral activity, has antibacterial, antitumor and antioxidant activity, has a molecular formula of C10H6O3, and has a molecular weight of 174.16. The SPI-112 is a protein tyrosine phosphatase inhibitor, the molecular formula of the SPI-112 is C22H17FN4O5S, and the molecular weight of the SPI-112 is 468.46. The inhibitor provided by the invention can be used for effectively reducing CTG trinucleotide repeated amplification in Mykylosing Dystrophy Type 1 (Mykylosing Dystrophy Type 1, DM1) by inhibiting the activity of TDP1 protein, and a new direction is provided for preparing a safe and effective medicine directly aiming at the CTG trinucleotide repeated amplification in DM1.

The present invention relates to a conjugate of a specific cell penetrating peptide covalently linked to a therapeutic antisense oligonucleotide having a nucleotide repeat sequence, suitable for treatment of repeat expansion based disorders, in particular myotonic dystrophy (DM1).

The present application relates to oligonucleotides (e.g., antisense oligonucleotides such as gapmers) designed to target DMPK RNAs and targeting complexes for delivering the oligonucleotides to cells (e.g., muscle cells) and uses thereof, particularly uses relating to treatment of disease. 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 DMPK.

Disclosed are purine derivatives of formulae (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods involving the inventive compounds or compositions for treating and / or preventing cell proliferative diseases including certain cancers of breast, brain, ovarian, lung, colorectal cancer, leukemias, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma and inflammatory and myotonic dystrophy type 1 diseases in a mammal. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of kinases, such as a cyclin-dependent kinases (CDK) (e.g., CDK12 / 13), and therefore, induce potent antiproliferative and apoptotic effects and / or inhibit transcription in the subject.

Delivery construct-oligonucleotide conjugates, pharmaceutical compositions, and their use for the treatment of myotonic dystrophy type 1 in a human subject are disclosed.

RNAi agents, compositions comprising RNAi agents, and methods for inhibiting the DM1 protein kinase (DMPK) gene are described. The DMPK RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of the DMPK gene. Pharmaceutical compositions comprising one or more DMPK RNAi agents, optionally together with one or more additional therapeutic agents, are also described. Delivery of the described DMPK RNAi agents to skeletal muscle cells in vivo results in the inhibition of DMPK gene expression and a reduction in DMPK protein levels, more specifically, a reduction in mutant DMPK-CUG protein levels, which can provide therapeutic benefits to subjects, including human subjects suffering from certain skeletal muscle-related diseases or disorders, including myotonic dystrophy type 1.

The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof, compositions thereof, and methods of using the same in methods of treating diseases, disorders, and conditions such as myotonic dystrophy type 1 (DM1).

Disclosed are muscle-selective promoter combinations and RNA-targeting gene therapy compositions and methods comprising the same for treating DM1.

The object of the present invention is to provide a pharmaceutical composition or a method that is effective for treating myotonic dystrophy type 1 (DM1). Provided is a therapeutic drug or method for DM1 that utilizes a modified PPR protein.

The present disclosure relates to RNA interference-based methods for inhibiting the expression of the dystrophia myotonia protein kinase (DMPK) gene. Recombinant adeno-associated viruses of the disclosure deliver DNAs encoding inhibitory RNAs that knock down the expression of DMPK or interfere with the expression of the CTG repeat associated with myotonic dystrophy type-1 (DM1). The methods have application in the treatment of myotonic dystrophies, including DM1, and other disorders associated with aberrant DMPK expression.

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

Provided herein are antibodies, portions thereof, and drug conjugates directed against cadherin 15. Also provided are nucleic acid sequences encoding the same; viral particles comprising the same, for example, for re-targeting viral particles to muscle cells; compositions comprising the same and methods of using the same, for example, for treating a subject in need thereof, in some embodiments, the composition may be used in a subject, such as a subject having a skeletal muscle related condition (e.g., X-linked myotubular myopathy (XLMTM), Duchenne muscular dystrophy (DMD), ankylosing muscular dystrophy (DMI), facial shoulder brachial muscular dystrophy type 1 (FSHD), congenital muscular dystrophy type 1 (MDC1A), limb girdle muscular dystrophy, anti-amyotrophy related glycoprotein disease, etc.) or rhabdomyosarcoma.

The invention is applicable to the technical field of molecular biology, and particularly provides a polynucleotide molecule combined with mRNA of a DMPK gene, the polynucleotide molecule comprises any one of nucleotide sequences of SEQ ID NO: 1 to SEQ ID NO: 200 and SEQ ID NO: 281 to SEQ ID NO: 490 or at least 12 continuous nucleotides in a nucleotide sequence complementary to the nucleotide sequence, and the polynucleotide molecule comprises at least 12 continuous nucleotides in any one of nucleotide sequences of SEQ ID NO: 1 to SEQ ID NO: 200 and any one of nucleotide sequences of SEQ ID NO: 281 to SEQ ID NO: 490. Or a sequence that differs from the at least 12 consecutive nucleotides by no more than 3 nucleotides, the nucleotides being in a modified or unmodified state. The polynucleotide molecules are complementary to the target sequence of DMPK and mediate RNA interference against the DMPK, thereby treating amyotrophy or ankylosing muscular dystrophy in a subject.