# US 2014/0194612 A1 · Immunosuppression compound and treatment method

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- Number: US 2014/0194612 A1
- Document ID: US20140194612A1
- Status: Published application
- Kind: A1
- Application number: 13/940,098
- Filed: 2013-07-11
- Published: 2014-07-10
- Earliest claimed: 2005-11-08
- Assignees: Sarepta Therapeutics, Inc.
- Applicants: Sarepta Therapeutics, Inc.
- Inventors: Dan V. Mourich; Patrick L. Iversen; Dwight D. Weller
- Web page: https://patentgrep.com/patent/US20140194612A1

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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)}
- C12N 2310/11: Antisense
- C12N 2310/314: Phosphoramidates
- C12N 2310/3233: Morpholino-type ring
- C12N 2310/3513: Protein; Peptide
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim at position 1

-16. (canceled)

### Claim 17

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.

### Claim 18 (depends on 17)

The oligonucleotide compound of claim 17, wherein the morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:
wherein Y1═O, Z═O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is an alkyl amine of the form NR2, where R is independently methyl or H.

### Claim 19 (depends on 17)

The oligonucleotide compound of claim 17, 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:
where Y1═O, Z═O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is an alkyl amine of the form NR2 for the uncharged linkages, where each R is independently hydrogen or methyl, and X is 1-piperazine, for the cationic linkages.

### Claim 20 (depends on 17)

The oligonucleotide compound of claim 17, 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.

### Claim 21 (depends on 20)

The oligonucleotide compound of claim 20, wherein the arginine-rich peptide comprises SEQ ID NO:16.

### Claim 22 (depends on 20)

The oligonucleotide compound of claim 20, wherein the arginine-rich peptide comprises SEQ ID NO:21.

### Claim 23 (depends on 17)

The oligonucleotide compound of claim 17, wherein the oligonucleotide compound comprises a sequence as set forth in any one of SEQ ID NOS:4-6.

### Claim 24 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound comprises SEQ ID NO:4.

### Claim 25 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound comprises SEQ ID NO:5.

### Claim 26 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound comprises SEQ ID NO:6.

### Claim 27 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound consists of SEQ ID NO:6.

### Claim 28 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound consists of SEQ ID NO:4.

### Claim 29 (depends on 23)

The oligonucleotide compound of claim 23, wherein the oligonucleotide compound consists of SEQ ID NO:5.