Details for Patent: 8,501,704

Title:	Immunosuppression compound and treatment method
Abstract:	Provided are methods and antisense oligonucleotide analogs for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection. The oligonucleotide analogs provided herein comprise a targeting sequence complementary to a preprocessed CTLA-4 mRNA region that spans the splice junction between intron 1 and exon 2 of the preprocessed CTLA-4 mRNA. Also provided are methods of use, in which the oligonucleotides are 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.degree. C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.
Inventor(s):	Mourich; Dan V. (Albany, OR), Iversen; Patrick L. (Corvallis, OR), Weller; Dwight D. (Corvallis, OR)
Assignee:	Sarepta Therapeutics, Inc. (Corvallis, OR)
Filing Date:	Nov 07, 2008
Application Number:	12/267,437
Claims:	1. A composition for suppressing an immune response in a subject, comprising (a) a pharmaceutically effective amount of a morpholino antisense oligonucleotide having between 12 and 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 having a targeting sequence that contains at least 12 contiguous bases that are complementary to SEQ ID NO: 22, the region of SEQ ID NO: 1 targeted by the overlapping sequences identified by SEQ ID NOS: 4-6, where the oligonucleotide is capable of forming with pre-processed cytotoxic T-lymphocyte antigen-4 (CTLA-4) mRNA, a heteroduplex structure characterized by a Tm of dissociation of at least 45.degree. C.; and (b) a pharmaceutically acceptable carrier. 2. The composition of claim 1, wherein said morpholino subunits in the antisense oligonucleotide are joined by phosphorodiamidate linkages, in accordance with the structure: ##STR00003## where Y.sub.1.dbd.O, Z.dbd.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 NR.sub.2, where R is independently methyl or H. 3. The composition of claim 1, in which at least 2 and no more than half of the total number of intersubunit linkages in the antisense oligonucleotide are cationic linkages, and wherein said morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure: ##STR00004## where Y.sub.1.dbd.O, Z.dbd.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 for the uncharged linkages is an alkyl amine of the form NR.sub.2, where each R is independently hydrogen or methyl, and for the cationic linkages, X is 1-piperazine. 4. The composition of claim 1, wherein the oligonucleotide is covalently linked to an arginine-rich peptide that comprises a sequence selected from SEQ ID NOS: 15-21. 5. The composition of claim 4, wherein the arginine-rich peptide comprises SEQ ID NO: 16. 6. The composition of claim 4, wherein the arginine-rich peptide comprises SEQ ID NO: 21. 7. The composition of claim 1, wherein the oligonucleotide comprises one of the overlapping sequences identified as SEQ ID NOS: 4-6. 8. The composition of claim 6, wherein the oligonucleotide comprises SEQ ID NO: 4. 9. A method of inducing immunological tolerance in a subject, comprising administering to the subject, a pharmaceutically effective amount of the compound of claim 1. 10. The method of claim 9, wherein said administering is by a parenteral route, in an amount between 5-250 mg compound/dose. 11. The method of claim 10, wherein said administering is by intravenous or intraperitoneal administration. 12. The method of claim 9, wherein the oligonucleotide has one of the overlapping sequences identified as SEQ ID NOS: 4-6. 13. The method of claim 9, wherein the oligonucleotide is covalently linked to an arginine-rich peptide that comprises a sequence selected from SEQ ID NOS: 15-21. 14. The method of claim 9, for use in delaying the onset of Type-1 diabetes in a subject. 15. The method of claim 14, wherein said administering is by a parenteral route, in an amount between 5-250 mg compound/dose. 16. The method of claim 15, wherein said administering is by intravenous or intraperitoneal administration.