Means and methods for counteracting muscle disorders
AssigneesBioMarin Technologies B.V., Academisch Ziekenhuis Leiden
InventorsJosephus Johannes De Kimpe, Gerard Johannes Platenburg, Judith Christina Theodora Van Deutekom, Annemieke Aartsma-Rus, Garrit-Jan Boudewijn Van Ommen
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Abstract
The invention provides means and methods for alleviating one or more symptom(s) of Duchenne Muscular Dystrophy and/or Becker Muscular Dystrophy. Therapies using compounds for providing patients with functional muscle proteins are combined with at least one adjunct compound for reducing inflammation, preferably for reducing muscle tissue inflammation, and/or at least one adjunct compound for improving muscle fiber function, integrity and/or survival.
Claims42
A composition comprising:
- a first compound that increases the level of a functional dystrophin protein produced in a muscle cell of a Duchenne Muscular Dystrophy (DMD) or Becker Muscular Dystrophy (BMD) individual,
- wherein said first compound is an antisense oligonucleotide that induces skipping of exon 51 of human dystrophin pre-mRNA of said individual;
- and a second compound comprising a steroid;
- wherein, upon administration to a DMD or BMD patient, the composition increases the ratio of said dystrophin to laminin-α2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-α2 in muscle tissue of a patient administered with said first compound and not said second compound;
- and
- wherein said antisense oligonucleotide is 100% complementary to a portion of exon 51 that is 13 to 50 nucleotides in length and wherein said oligonucleotide comprises a non naturally-occurring modification.
A method for alleviating one or more symptom(s) of Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in an individual, the method comprising administering to a DMD or BMD patient:
- a first compound that increases the level of a functional dystrophin protein produced in a muscle cell of said individual in said individual,
- wherein said first compound is an antisense oligonucleotide that induces skipping of exon 51 of dystrophin pre-mRNA of said individual, and
- a second compound, comprising a steroid;
- wherein, upon administration to a DMD or BMD patient, the composition increases the ratio of said dystrophin to laminin-α2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-α2 in muscle tissue of a patient administered with said first compound and not said second compound;
- and
- wherein said antisense oligonucleotide is 100% complementary to a portion of exon 51 that is 13 to 50 nucleotides in length and wherein said oligonucleotide comprises a non naturally-occurring modification.
A method for increasing the production of a functional dystrophin protein in a cell, said cell comprising pre-mRNA of a dystrophin gene encoding an aberrant dystrophin protein comprising:
- providing said cell with a first compound for inhibiting inclusion of exon 51 into mRNA produced from splicing of said dystrophin pre-mRNA, wherein said first compound is an antisense oligonucleotide that induces the skipping of exon 51 of the human dystrophin pre-mRNA, and providing said cell with a second compound comprising a steroid,
- said method further comprising allowing translation of mRNA produced from splicing of said pre-mRNA;
- wherein, upon administration to a DMD or BMD patient, the composition increases the ratio of said dystrophin to laminin-α2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-α2 in muscle tissue of a patient administered with said first compound and not said second compound;
- and
- wherein said antisense oligonucleotide is 100% complementary to a portion of exon 51 that is 13 to 50 nucleotides in length and wherein said oligonucleotide comprises a non naturally-occurring modification.
A method for alleviating one or more symptoms of Duchenne muscular dystrophy in a human patient, comprising administering to the patient an antisense oligonucleotide that is:
- (a) 100% complementary to a portion of exon 51 of the human dystrophin pre-mRNA and (b) 30 nucleotides in length,
- wherein the antisense oligonucleotide comprises the sequence 5′-CUC CAA CAU CAA GGA AGA UGG CAU UUC UAG-3′ (SEQ ID NO:193),
- wherein the antisense oligonucleotide is a morpholino phosphorodiamidate,
- wherein the antisense oligonucleotide is administered intravenously,
- wherein the antisense oligonucleotide induces skipping of exon 51 of dystrophin pre-mRNA, and
- wherein the patient is receiving glucocorticosteroid treatment.
A method for alleviating one or more symptoms of Duchenne muscular dystrophy in a human patient, comprising administering to the patient an antisense oligonucleotide that is:
- (a) 100% complementary to a portion of exon 51 of the human dystrophin pre-mRNA and (b) 30 nucleotides in length,
- wherein the antisense oligonucleotide is a functional equivalent of an oligonucleotide comprising the sequence 5′-CUC CAA CAU CAA GGA AGA UGG CAU UUC UAG-3′ (SEQ ID NO:193),
- wherein the antisense oligonucleotide is a morpholino phosphorodiamidate,
- wherein the antisense oligonucleotide is administered intravenously,
- wherein the antisense oligonucleotide induces skipping of exon 51 of dystrophin pre-mRNA, and
- wherein the patient is receiving glucocorticosteroid treatment.
A method for alleviating one or more symptoms of Duchenne muscular dystrophy in a human patient, comprising administering to the patient an antisense oligonucleotide that is 100% complementary to the portion of exon 51 of the human dystrophin pre-mRNA to which the sequence 5′-CUC CAA CAU CAA GGA AGA UGG CAU UUC UAG-3′ (SEQ ID NO:193) is complementary,
- wherein the antisense oligonucleotide is 30 nucleotides in length,
- wherein the antisense oligonucleotide is a morpholino phosphorodiamidate,
- wherein the antisense oligonucleotide is administered intravenously,
- wherein the antisense oligonucleotide induces skipping of exon 51 of dystrophin pre-mRNA, and
- wherein the patient is receiving glucocorticosteroid treatment.
A method for alleviating one or more symptoms of Duchenne muscular dystrophy in a human patient, comprising administering to the patient an antisense oligonucleotide that is 100% complementary to the portion of exon 51 of the human dystrophin pre-mRNA to which the sequence 5′-CUC CAA CAU CAA GGA AGA UGG CAU UUC UAG-3′ (SEQ ID NO:193) is complementary,
- wherein the antisense oligonucleotide is 30 nucleotides in length,
- wherein the antisense oligonucleotide is a morpholino phosphorodiamidate,
- wherein the antisense oligonucleotide is administered intravenously,
- wherein the antisense oligonucleotide induces skipping of exon 51 of dystrophin pre-mRNA,
- wherein the patient is receiving glucocorticosteroid treatment, wherein the glucocorticosteroid is selected from prednisone and deflazacort, and
- wherein the method increases the ratio of dystrophin to laminin-α2 in muscle tissue of the patient as compared to the ratio of dystrophin to laminin-α2 in muscle tissue of a similar patient treated with the antisense oligonucleotide and not the glucocorticosteroid.
Dependencies are inferred from the claim text.