Splice-region antisense composition and method

• US 9,416,361 B2
• Filed: 11/06/2014
• Issued: 08/16/2016
• Est. Priority Date: 05/04/2000
• Status: Expired due to Term

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Iversen, Patrick L., Hudziak, Robert
• Primary Examiner(s): Bowman, Amy
• Application Number:
  US14/535,098
• Publication Number:
  US 20150232839A1
• Time in Patent Office: 649 Days
• US Class Current: 1/1
• 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. 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;

2. The oligomer of claim 1, wherein the 5′

terminal morpholino subunit is of a formula;

3. The oligomer of claim 1, wherein the oligomer is of a formula:

4. The oligomer of claim 1, wherein each R¹ is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.

5. The oligomer of claim 3, wherein each R¹ is methyl.

6. The oligomer of claim 3, wherein R³ is H.

7. The oligomer of claim 3, wherein each R¹ is methyl, and R³ is H.

8. The oligomer of claim 3, wherein each P is independently selected from adenine, cytosine, guanine, uracil, and thymine.

10. The oligomer of claim 1, wherein the oligomer is of a formula:

11. The oligomer of claim 10, wherein each R¹ is independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, and t-butyl.

12. The oligomer of claim 10, wherein each R¹ is methyl.

13. The oligomer of claim 10, wherein R³ is H.

14. The oligomer of claim 10, wherein each R¹ is methyl, and R³ is H.

15. The oligomer of claim 10, wherein each P is independently selected from adenine, cytosine, guanine, uracil, and thymine.

9. A compound of formula:

16. A compound of formula: