Claims for Patent: 8,168,775

Summary for Patent: 8,168,775

Title:	Compositions and methods for inhibiting expression of transthyretin
Abstract:	The invention relates to a double-stranded ribonucleic acid (dsRNA) targeting a transthyretin (TTR) gene, and methods of using the dsRNA to inhibit expression of TTR.
Inventor(s):	Sah; Dinah Wen-Yee (Boston, MA), Hinkle; Gregory (Plymouth, MA), Alvarez; Rene (Cambridge, MA), Milstein; Stuart (Cambridge, MA), Chen; Qingmin (Lincoln, MA)
Assignee:	Alnylam Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	12/582,669
Patent Claims:	1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of transthyretin (TTR), wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region complementary to a part of a mRNA encoding transthyretin (TTR), wherein said region of complementarity is 19 nucleotides in length in length and the antisense strand comprises SEQ ID NO:170 and each strand of the dsRNA is 19, 20, 21, 22, 23, or 24 nucleotides in length. 2. The dsRNA of claim 1, wherein the sense strand consists of SEQ ID NO:449 and the antisense strand consists of SEQ ID NO:450. 3. The dsRNA of claim 1, wherein the sense strand consists of SEQ ID NO:729 and the antisense strand consists of SEQ ID NO:730. 4. The dsRNA of claim 1, wherein the sense strand consists of SEQ ID NO:1009 and the antisense strand consists of SEQ ID NO:1010. 5. The dsRNA of claim 1, wherein the region of complementary consists of SEQ ID NO:169. 6. The dsRNA of claim 1, wherein each strand is 21 nucleotides in length. 7. The dsRNA of claim 1, wherein the dsRNA does not cleave a TTR mRNA between the adenine nucleotide at position 637 of SEQ ID NO:1331 and the guanine nucleotide at position 638 of SEQ ID NO:1331. 8. The dsRNA of claim 1, wherein the dsRNA cleaves a TTR mRNA between the guanine nucleotide at position 636 of SEQ ID NO:1331 and the adenine nucleotide at position 637 of SEQ ID NO:1331. 9. The dsRNA of claim 1, wherein the dsRNA anneals to a TTR mRNA between the guanine nucleotide at position 628 of SEQ ID NO:1331 and the uracil nucleotide at position 646 of SEQ ID NO: 1331. 10. The dsRNA of claim 1, wherein said dsRNA comprises at least one modified nucleotide. 11. The dsRNA of claim 10, wherein at least one of said modified nucleotides is chosen from the group of: a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 12. The dsRNA of claim 10, wherein said modified nucleotide is chosen from the group of: a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 13. The dsRNA of claim 10, comprising at least one 2'-O-methyl modified nucleotide. 14. The dsRNA of claim 1, wherein the dsRNA is conjugated to a ligand. 15. The dsRNA of claim 1, wherein administration of the dsRNA to a cell results in about 95% inhibition of TTR mRNA expression as measured by a real time PCR assay, wherein the cell is a HepG2 cell or a Hep3B cell, and wherein the concentration of the dsRNA is 10 nM. 16. The dsRNA of claim 1, wherein said antisense strand base pairs with the guanine at position 628 of SEQ ID NO:1331. 17. A cell containing the dsRNA of claim 1. 18. A vector comprising a nucleotide sequence that encodes at least one strand of the dsRNA of claim 1. 19. A cell comprising the vector of claim 18. 20. A pharmaceutical composition for inhibiting expression of a TTR gene comprising the dsRNA of claim 1 and a pharmaceutically acceptable carrier. 21. A method of inhibiting TTR expression in a cell, the method comprising: (a) contacting the cell with the dsRNA of claim 1; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the cell. 22. A pharmaceutical composition for inhibiting expression of a TTR gene comprising the dsRNA of claim 4 and a pharmaceutically acceptable carrier. 23. A method of inhibiting TTR expression in a cell, the method comprising: (a) contacting the cell with the dsRNA of claim 4; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the cell.