Details for Patent: 9,487,786

Title:	Immunosuppression compound and treatment method
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.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:	Dec 23, 2014
Application Number:	14/581,485
Claims:	1. A phosphorodiamidate morpholino antisense oligonucleotide of 12 to 40 bases comprising a base sequence that is 100% complementary to contiguous bases of human CTLA-4 pre-mRNA, wherein the base sequence comprises at least 12 contiguous bases that are 100 complementary to SEQ ID NO: 22, and wherein the phosphorodiamidate morpholino antisense oligonucleotide induces skipping of exon 2 of the human CTLA-4 pre-mRNA. 2. The phosphorodiarnidate morpholino antisense oligonucleotide of claim 1, wherein the oligonucleotide is of 15 to 25 bases. 3. The phosphorodiamidate morphohno antisense oligonucleotide of claim 2, wherein the base sequence comprises at least 15 consecutive bases that are 100% complementary to SEQ ID NO: 22. 4. The phosphorodiamidate morpholino antisense oligonucleotide of claim 1, further comprising a polyethylene glycol moiety. 5. The phosphorodiamidate morpholino antisense oligonucleotide of claim 1, wherein the phosphorodiamidate morpholino antisense oligonucleotide comprises phosphorus-containing intersubunit 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 form the NR.sub.2, where R is independently methyl or H. 6. The phosphorodiamidate morpholino antisense oligonucleotide of claim 5, wherein X is 1-piperazine for at least 2 and no more than half of the total number of phosphorus-containing intersubunit linkages in the phosphorodiamidate morpholino antisense oligonucleotide. 7. The phosphorodiamidate morpholino antisense oligonucleotide of claim 1, wherein the phosphorodiamidate morpholino antisense oligonucleotide is linked to an arginine-rich peptide. 8. A pharmaceutical composition comprising: (a) a phosphorodiamidate morpholino antisense oligonucleotide of 12 to 40 bases comprising a base sequence that is 100% complementary to contiguous bases of human CTLA-4 pre-mRNA, wherein the base sequence comprises at least 12 contiguous bases that are 100% complementary to SEQ ID NO: 22, the region of SEQ ID NO: 1 targeted by the overlapping sequences identified by SEQ ID NOS: 46, and wherein the phosphorodiamidate morpholino antisense oligonucleotide induces skipping of exon 2 of the human CTLA-4 pre-mRNA; and (b) pharmaceutically acceptable carrier. 9. The pharmaceutical composition of claim 8, wherein the phosphorodiamidate morpholino antisense oligonucleotide is of 15 to 25 bases. 10. The pharmaceutical composition of claim 9, wherein the base sequence comprises at least 15 consecutive bases that are 100% complementary to SEQ ID NO 22. 11. The pharmaceutical composition of claim 8, further comprising a polyethylene glycol moiety. 12. The pharmaceutical composition of claim 8, wherein the phosphorodiamidate morpholino antisense oligonucleotide comprises phosphorus-containing intersubunit 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 is an alkyl amine of form the NR.sub.2, where R is independently methyl or H. 13. The phosphorodiami date morpholino antisense oligonucleotide of claim 12, wherein X is 1-piperazine for at least 2 and no more than half of the total number of phosphorus-containing intersubutnit linkages in the phosphorodianiidate morphohno antisense oligonucleotide. 14. The phosphorodiamidate morpholino antisense oligonucleotide of claim 8, wherein the phosphorodiamidate morpholino antisense oligonucleotide is linked to an arginine-rich peptide. 15. A morpholino antisense oligonucleotide of 12 to 40 bases comprising a base sequence that is 100% complementary to SEQ ID N0: 22, wherein the morpholino antisense oligonucleotide induces skipping of exon 2 of CTLA-4 pre-mRNA. 16. The morpholino antisense oligonucleotide of claim 15, wherein the oligonucleotide is of 15 to 25 bases. 17. The morpholino antisense oligonucleotide of claim 15, wherein the oligonucleotide is of 18 to 25 bases. 18. The morpholino antisense oligonucleotide of claim 15, further comprising a polyethylene glycol moiety. 19. The morpholino antisense oligonucleotide of claim 15, wherein the morpholino antisense oligonucleotide comprises phosphorus-containing intersubunit linkages in accordance with the structure: ##STR00005## 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 selected from alkyl, alkoxy, thioalkoxy, and alkyl amino. 20. The morpholino antisense oligonucleotide of claim 19, wherein X is 1-piperazine for at least 2 and no more than half of the total number of phosphorus-containing intersubunit linkages in the morpholino antisense oligonucleotide. 21. The morpholino anti sense oligonucleotide of claim 15, wherein the morpholino antisense oligonucleotide is linked to an arginine-rich peptide.