Claims for Patent: RE48468

Summary for Patent: RE48468

Title:	Means and methods for counteracting muscle disorders
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.
Inventor(s):	De Kimpe; Josephus Johannes (Utrecht, NL), Platenburg; Gerard Johannes (Voorschoten, NL), Van Deutekom; Judith Christina Theodora (Dordrecht, NL), Aartsma-Rus; Annemieke (Hoofddorp, NL), Van Ommen; Garrit-Jan Boudewijn (Amsterdam, NL)
Assignee:	BioMarin Technologies B.V. (Leiden, NL) Academisch Ziekenhuis Leiden (Leiden, NL)
Application Number:	15/881,574
Patent Claims:	1. 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-.alpha.2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-.alpha.2 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..]. .[.2. The composition of claim 1, wherein said antisense oligonucleotide is 100% complementary to a portion of exon 51 that is 14 to 25 nucleotides in length..]. .[.3. The composition of claim 1, wherein said antisense oligonucleotide is 100% complementary to a portion of exon 51 that is 20 to 25 nucleotides in length..]. .[.4. The composition of claim 1, wherein said oligonucleotide comprises one or more ribonucleotides, and wherein a said ribonucleotide contains a modification..]. .[.5. The composition of claim 4, wherein said modification is a 2'-O-methyl modified ribose..]. .[.6. The composition of claim 1, wherein said modification is selected from the group consisting of at least one of a peptide nucleic acid, a locked nucleic acid, and morpholino phosphorodiamidate..]. .[.7. 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-.alpha.2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-.alpha.2 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..]. .[.8. The method of claim 7, wherein said oligonucleotide comprises one or more ribonucleotides, and wherein a said ribonucleotide contains a modification..]. .[.9. The method of claim 8, wherein said modification is selected from the group consisting of a 2'-O-methyl modified ribose..]. .[.10. The method of claim 7, wherein said modification is selected from the group consisting of at least one of a peptide nucleic acid, a locked nucleic acid, and morpholino phosphorodiamidate..]. .[.11. 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-.alpha.2 in muscle tissue of said patient as compared to the ratio of said dystrophin to laminin-.alpha.2 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..]. .[.12. A pharmaceutical preparation comprising: said first compound according to claim 1, said second compound according to claim 1, comprising a steroid, and a pharmaceutically acceptable carrier, adjuvant, diluent and/or excipient..]. .[.13. A kit comprising: said first compound according to claim 1, and said second compound according to claim 1..]. .[.14. The kit of claim 13, further comprising a pharmaceutically acceptable carrier, adjuvant, diluent and/or excipient..]. .[.15. The kit of claim 13, further comprising packaging means thereof..]. .[.16. The composition according to claim 1, wherein the oligonucleotide comprises a phosphorothioate internucleotide linkage, a 2'-O-methyl ribose and/or a LNA..]. .[.17. The kit according to claim 13, wherein the oligonucleotide comprises a phosphorothioate internucleotide linkage, a 2'-O-methyl ribose and/or a LNA..]. .[.18. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier, adjuvant, diluent, and/or excipient..]. .[.19. The method of claim 7 wherein said steroid is a glucocorticosteroid..]. .[.20. The method of claim 19 wherein said glucocorticosteroid is selected from a group consisting of prednisone, dexamethasone, prednizolone and deflazacort..]. .[.21. The method of claim 20 wherein said prednisone is present at a dosage of 0.5-1.0 mg/kg..]. .[.22. The method of claim 20 wherein said deflazacort is present at a dosage of 0.4-1.4 mg/kg..]. .Iadd.23. 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..Iaddend. .Iadd.24. The method of claim 23, wherein the patient was receiving the glucocorticosteroid treatment prior to the administration of the antisense oligonucleotide..Iaddend. .Iadd.25. The method of claim 24, wherein the prior glucocorticosteroid treatment was for a period of at least three weeks..Iaddend. .Iadd.26. The method of claim 23, wherein the glucocorticosteroid is selected from the group consisting of prednisone, dexamethasone, prednisolone, and deflazacort..Iaddend. .Iadd.27. The method of claim 26, wherein the glucocorticosteroid is prednisone..Iaddend. .Iadd.28. The method of claim 27, wherein the patient is receiving the prednisolone at a dose of about 0.5 mg/kg/day to about 1.0 mg/kg/day..Iaddend. .Iadd.29. The method of claim 26, wherein the glucocorticosteroid is deflazacort..Iaddend. .Iadd.30. The method of claim 29, wherein the patient is receiving the deflazacort at a dose of about 0.4 mg/kg/day to about 1.4 mg/kg/day..Iaddend. .Iadd.31. The method of claim 23, wherein the method increases the ratio of dystrophin to laminin-.alpha.2 in muscle tissue of the patient as compared to the ratio of dystrophin to laminin-.alpha.2 in muscle tissue of a similar patient treated with the antisense oligonucleotide and not the glucocorticosteroid..Iaddend. .Iadd.32. 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..Iaddend. .Iadd.33. 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..Iaddend. .Iadd.34. The method of claim 33, wherein the patient has received the glucocorticosteroid treatment prior to the administration of the antisense oligonucleotide..Iaddend. .Iadd.35. The method of claim 34, wherein the prior glucocorticosteroid treatment was for a period of at least three weeks..Iaddend. .Iadd.36. The method of claim 33, wherein the glucocorticosteroid is selected from the group consisting of prednisone, dexamethasone, prednisolone, and deflazacort..Iaddend. .Iadd.37. The method of claim 36, wherein the glucocorticosteroid is prednisone..Iaddend. .Iadd.38. The method of claim 37, wherein the patient is receiving the prednisone at a dose of about 0.5 mg/kg/day to about 1.0 mg/kg/day..Iaddend. .Iadd.39. The method of claim 36, wherein the glucocorticosteroid is deflazacort..Iaddend. .Iadd.40. The method of claim 39, wherein the patient is receiving the deflazacort at a dose of about 04. Mg/kg/day to about 1.4 mg/kg/day..Iaddend. .Iadd.41. The method of claim 33, wherein the method increases the ratio of dystrophin to laminin-.alpha.2 in muscle tissue of the patient as compared to the ratio of dystrophin to laminin-.alpha.2 in muscle tissue of a similar patient treated with the antisense oligonucleotide and not the glucocorticosteroid..Iaddend. .Iadd.42. 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-.alpha.2 in muscle tissue of the patient as compared to the ratio of dystrophin to laminin-.alpha.2 in muscle tissue of a similar patient treated with the antisense oligonucleotide and not the glucocorticosteroid..Iaddend.