Immunosuppression compound and treatment method

• US 8,933,216 B2
• Filed: 07/11/2013
• Issued: 01/13/2015
• Est. Priority Date: 11/08/2005
• Status: Expired due to Fees

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Mourich, Dan V., Iversen, Patrick L., Weller, Dwight D.
• Primary Examiner(s): GIBBS, TERRA C
• Application Number:
  US13/940,098
• Publication Number:
  US 20140194612A1
• Time in Patent Office: 551 Days
• Field of Search: 514/44, 536/24.5
• US Class Current: 536/24.5
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/3513 Protein; Peptide

Abstract

A method and compound for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection are disclosed. The compound is an antisense oligonucleotide analog compound having a targeting sequence complementary to a preprocessed CTLA-4 mRNA region identified by SEQ ID NO: 22 in SEQ ID NO: 1, spanning the splice junction between intron 1 and exon 2 of the preprocessed mRNA of the subject. The compound is effective, when administered to a subject, to form within host cells, a heteroduplex structure (i) composed of the preprocessed CTLA-4 mRNA and the oligonucleotide compound, (ii) characterized by a Tm of dissociation of at least 45° C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.

Claims

1. A cytotoxic T-lymphocyte antigen-4 (CTLA-4) antisense oligonucleotide analog compound, comprising a targeting sequence of at least 12 contiguous bases that correspond to a sequence located within the sequence spanning from the 5′

-end of SEQ ID NO;

4 to the 3′

-end of SEQ ID NO;

6, wherein the oligonucleotide compound contains from 12 to 40 morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′

-exocyclic carbon of an adjacent subunit, and is capable of forming a heteroduplex structure with a pre-processed CTLA-4 mRNA having a Tm of dissociation of at least 45°

C.

2. The oligonucleotide compound of claim 1, wherein the morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:

3. The oligonucleotide compound of claim 1, wherein at least two and no more than half of the total number of intersubunit linkages in the oligonucleotide compound are cationic linkages, and wherein the morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:

4. The oligonucleotide compound of claim 1, wherein the oligonucleotide compound is covalently linked to an arginine-rich peptide comprising a sequence as set forth in any one of SEQ ID NOS:

15-21.

5. The oligonucleotide compound of claim 4, wherein the arginine-rich peptide comprises SEQ ID NO:

16.

6. The oligonucleotide compound of claim 4, wherein the arginine-rich peptide comprises SEQ ID NO:

21.

7. The oligonucleotide compound of claim 1, wherein the oligonucleotide compound comprises a sequence as set forth in any one of SEQ ID NOS:

4-6.

8. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound comprises SEQ ID NO:

4.

9. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound comprises SEQ ID NO:

5.

10. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound comprises SEQ ID NO:

6.

11. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound consists of SEQ ID NO:

6.

12. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound consists of SEQ ID NO:

4.

13. The oligonucleotide compound of claim 7, wherein the oligonucleotide compound consists of SEQ ID NO:

5.