SPLICE-REGION ANTISENSE COMPOSITION AND METHOD

• US 20180237773A1
• Filed: 10/03/2017
• Published: 08/23/2018
• Est. Priority Date: 05/04/2000
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Iversen, Patrick L., Hudziak, Robert
• Granted Patent: US 10,533,174 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1132 against retroviridae, e.g. HIV
• CPC Class Codes: C12N 15/1135 : against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1136 : against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 15/1138 : against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 : Antisense
• CPC Class Codes: C12N 2310/314 : Phosphoramidates
• CPC Class Codes: C12N 2310/3145 : with the nitrogen in 3' or 5'-position
• CPC Class Codes: C12N 2310/3233 : Morpholino-type ring
• CPC Class Codes: C12N 2320/33 : Alteration of splicing

Abstract

Antisense compositions targeted against an mRNA sequence coding for a selected protein, at a region having its 5′ end from 1 to about 25 base pairs downstream of a normal splice acceptor junction in the preprocessed mRNA, are disclosed. The antisense compound is RNase-inactive, and is preferably a phosphorodiamidate-linked morpholino oligonucleotide. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.

Claims

1-38. -38. (canceled)

39. A pharmaceutical composition comprising an oligomer of 8 to 40 morpholino subunits connected by phosphorous-containing intersubunit linkages, wherein the 5′

terminal morpholino subunit comprises a group of the formula;

40. The pharmaceutical composition of claim 39, wherein the 5′

terminal morpholino subunit of the oligomer is of a formula;

41. The pharmaceutical composition of claim 39, wherein the oligomer is of a formula:

42. The pharmaceutical composition of claim 41, wherein each R¹ is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.

43. The pharmaceutical composition of claim 41, wherein each R¹ is methyl.

44. The pharmaceutical composition of claim 41, wherein each P_i is independently selected from adenine, cytosine, guanine, uracil, and thymine.

45. The pharmaceutical composition of claim 39, wherein the pharmaceutical composition is formulated for intravenous administration.

46. The pharmaceutical composition of claim 39, wherein the oligomer is of a formula:

47. The pharmaceutical composition of claim 46, wherein each R¹ is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.

48. The pharmaceutical composition of claim 46, wherein each R¹ is methyl.

49. The pharmaceutical composition of claim 46, wherein each P_i is independently selected from adenine, cytosine, guanine, uracil, and thymine.

50. A pharmaceutical composition comprising a compound of formula:

51. A pharmaceutical composition comprising a compound of formula: