34 results about "Myotonic dystrophy" patented technology

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).

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 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 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.

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.

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.

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.

The disclosure features compositions and methods for the treatment of trinucleotide repeat expansion disorders. The compositions described herein that may be used to treat such disorders include at least one nucleic acid construct comprising a first nucleic acid sequence. In some embodiments, the first nucleic acid sequence encodes a therapeutic protein. In some embodiments, the first nucleic acid sequence encodes a MBNL protein. In some embodiments, the first nucleic acid sequence encodes MBNL1 protein. The composition may comprise at least one nucleic acid construct comprising a second nucleic acid. In some embodiments, the second nucleic acid sequence encodes an interfering RNA construct that suppresses the expression of RNA transcripts containing aberrantly expanded repeat regions. Disclosed herein are also methods of increasing the presence of functional muscleblind-like protein (MBNL) in the nucleus of a cell with expression control in tissue types and methods of treating muscular dystrophy or spliceopathy using the compositions disclosed herein.

Disclosed are methods of treating a subject having myotonic dystrophy type 1 (DM1). The methods include administering a therapeutic regimen including a plurality of doses of a conjugate spaced at a time interval of at least 1 month, where the conjugate includes an oligonucleotide and a peptide covalently bonded or linked via a linker to the oligonucleotide, the peptide including a hydrophobic domain flanked by two cationic domains, each of the cationic domains including one of RBRRBRR (SEQ ID NO: 1), RBRBR (SEQ ID NO: 2), RBRR (SEQ ID NO: 3), RBRRBR (SEQ ID NO: 4), RRBRBR (SEQ ID NO: 5), RBRRB (SEQ ID NO: 6), BRBR (SEQ ID NO: 7), RBHBH (SEQ ID NO: 8), HBHBR (SEQ ID NO: 9), RBRHBHR (SEQ ID NO: 10), RBRBBHR (SEQ ID NO: 11), RBRRBH (SEQ ID NO: 12), HBRRBR (SEQ ID NO: 13), HBHBH (SEQ ID NO: 14), BHBH (SEQ ID NO: 15), BRBSB (SEQ ID NO: 16), BRB[Hyp]B (SEQ ID NO: 17), R[Hyp]H[Hyp]HB (SEQ ID NO: 18), and R[Hyp]RR[Hyp]R (SEQ ID NO: 19), and the hydrophobic domain including one of YQFLI (SEQ ID NO: 20), FQILY (SEQ ID NO: 21), ILFQY (SEQ ID NO: 22), FQIY (SEQ ID NO: 23), VWVW, WWPWW (SEQ ID NO: 24), WPWW (SEQ ID NO: 25), and VWVPW (SEQ ID NO: 26); and the oligonucleotide including a total of 12 to 40 contiguous nucleobases, where at least 9 contiguous nucleobases are complementary to a CUG repeat sequence.

Provided herein are compositions and methods for retargeting viral particles. e.g. adeno-associated virus (AAV) particles, to muscle cells using muscle-specific surface proteins. AAV adapted accordingly may be a viable gene therapy platform for the treatment of a skeletal muscle related disorder (e.g., X-linked myotubular myopathy (XLMTM). Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM1), Facioscapulohumeral muscular dystrophy Type 1 (FSHD), congenital muscular dystrophy type 1A (MDC1A), Limb girdle muscular dystrophy, dystroglycanopathy, etc.) in a patient in need thereof.

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

The present disclosure provides the use of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) in treating a neurological disease associated with repeat expansions and / or RAN protein accumulation, reducing the level of one or more repeat associated non-ATG (RAN) proteins, and reducing the accumulation of RAN proteins in a subject and / or biological sample. Also provided is the use of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) in inhibiting RAN protein translation in a subject and in a biological sample (e.g., cells, tissue). Also provided in the present disclosure are pharmaceutical compositions, kits, and uses of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) for treating diseases associated with repeat expansions. Exemplary diseases associated with repeat expansions include, but are not limited to, C9ORFf72 amyotrophic lateral sclerosis (ALS), or C9ORFf72 frontotemporal dementia; myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); spinocerebellar ataxia; Huntington's disease; Fragile X Tremor Ataxia Syndrome (FXTAS); and Fragile XE syndrome (FRAXE).

The application discloses an inhibitor acting on a TDP1 target point and application thereof. The active ingredient of the inhibitor comprises Lawsone (2-hydroxy-1, 4-naphthoquinone) or SPI-112. The Lawsone is an orally active naphthoquinone compound, has antibacterial, antitumor and antioxidant activity, and has a molecular formula of C 10 H6O3 and a molecular weight of 174.16. The SPI-112 is a protein tyrosine phosphatase inhibitor, has a molecular formula of C 22 H 17 FN4O5S and a molecular weight of 468.46. The inhibitor provided by the application can effectively reduce CTG trinucleotide repeat expansion in myotonic dystrophy type 1 (DM1) by inhibiting TDP1 protein activity, and provides a new direction for preparing a safe and effective drug directly aiming at the CTG trinucleotide repeat expansion in DM1.

The present invention belongs to the field of biomedicine, and specifically relates to an siRNA, its antibody conjugate, product and application. The sense strand of the siRNA of the present invention is the sequence shown in SEQ ID NO: 17, and the antisense strand is the sequence shown in SEQ ID NO: 18; the present invention also provides an siRNA antibody conjugate prepared by a site-specific conjugation method, including an antibody, a linker and siRNA, and the siRNA is preferably a modified siRNA; the modified nucleotide is selected from one or more of 2'-position sugar moiety modification, phosphate group modification or nucleotide analogue modification. The siRNA antibody conjugate of the present invention can reduce the expression of DMPK mRNA in human skeletal muscle cells HSKMC and human bladder transitional cell papilloma cells RT4, and has great significance for the treatment of DM1 type myotonic dystrophy disease.

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

This application relates to oligonucleotides (e.g., antisense oligonucleotides such as gapmers) designed to target DMPK RNA, and targeting complexes for delivering oligonucleotides to cells (e.g., muscle cells), and their uses, particularly for the treatment of disease. In some embodiments, the muscle targeting agent specifically binds to an internalized cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of DMPK.

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).

To provide recombinant virus products and methods for inhibiting the expression of the dystrophia myotonica protein kinase and / or interfering with the trinucleotide repeat expansion in the 3'-untranslated region of the DMPK gene.SOLUTION: The present disclosure relates to RNA interference-based methods for inhibiting the expression of the dystrophia myotonica 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 treatment of myotonic dystrophy, including DM1, and other disorders associated with aberrant DMPK expression.SELECTED DRAWING: None

RNAi molecules for treating myotonic dystrophy type 1 (DM1) are provided herein. Furthermore, expression cassettes, vectors (e.g., rAAV), viral particles, and pharmaceutical compositions containing RNAi are provided herein. Moreover, methods and kits related to the use of RNAi for treating DM1, for example, are provided herein.

Provided herein, in certain aspects, are pharmaceutical compositions comprising an HSA-IGF2 fusion protein formulated for subcutaneous administration. As provided herein, are methods of treating muscle disorders, including myotonic dystrophies, comprising administration of a pharmaceutical composition comprising an HSA-IGF2 fusion protein formulated for subcutaneous administration.