US 11,725,207 B2
Serpina1 iRNA compositions and methods of use thereof
Mark K. Schlegel, Boston, MA (US); Maja Janas, Cambridge, MA (US); Vasant R. Jadhav, Sharon, MA (US); Donald Foster, Attleboro, MA (US); Muthiah Manoharan, Weston, MA (US); Kallanthottathil G. Rajeev, Wayland, MA (US); Alexander V. Kel'in, Swampscott, MA (US); Klaus Charisse, Acton, MA (US); Jayaprakash K. Nair, Cambridge, MA (US); Martin A. Maier, Belmont, MA (US); Shigeo Matsuda, Cambridge, MA (US); Muthusamy Jayaraman, Cambridge, MA (US); Alfica Sehgal, Medford, MA (US); Christopher Brown, Cambridge, MA (US); Kevin Fitzgerald, Brookline, MA (US); and Stuart Milstein, Arlington, MA (US)
Assigned to Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
Filed by Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
Filed on Mar. 8, 2021, as Appl. No. 17/194,431.
Application 17/194,431 is a division of application No. 16/420,263, filed on May 23, 2019, granted, now 10,995,336, issued on May 4, 2021.
Application 16/420,263 is a continuation of application No. PCT/US2017/062701, filed on Nov. 21, 2017.
Claims priority of provisional application 62/561,514, filed on Sep. 21, 2017.
Claims priority of provisional application 62/549,099, filed on Aug. 23, 2017.
Claims priority of provisional application 62/548,589, filed on Aug. 22, 2017.
Claims priority of provisional application 62/425,907, filed on Nov. 23, 2016.
Prior Publication US 2021/0269796 A1, Sep. 2, 2021
Int. Cl. C12N 15/113 (2010.01)
CPC C12N 15/113 (2013.01) [C12N 2310/14 (2013.01); C12N 2310/315 (2013.01); C12N 2310/351 (2013.01)] 123 Claims
 
1. A method of inhibiting serine peptidase inhibitor, Glade A, member 1 (Serpina1) expression in a cell, the method comprising contacting the cell with a double stranded RNA (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of
 
 (SEQ ID NO: 419)
 
 5′-UUUUGUUCAAUCAUUAAGAAGAC-3′,
wherein all of the nucleotides of the antisense strand comprise a nucleotide modification,
wherein the antisense strand comprises at least one thermally destabilizing modification selected from the group consisting of an abasic modification, a mismatch with the opposing nucleotide in the opposing strand, a 2′-deoxy modification, and an acyclic nucleotide modification at position 4, 5, 6, 7 and/or 8 from the 5′-end,
wherein the nucleotides at positions 2, 6, 8, 9, 14, and 16, or at positions 2, 6, 14, and 16, or at positions 2, 14, and 16 from the 5′-end of the antisense strand comprise a 2′-F nucleotide modification,
wherein all of the nucleotides of the sense strand comprise a nucleotide modification,
wherein the nucleotides at positions 7, 9, 10, and 11, or at positions 7, 10, and 11 from the 5′-end of the sense strand comprise a 2′-F nucleotide modification,
wherein the sense strand comprises an ASGPR ligand, and
wherein each of the sense strand and the antisense strand are independently 19 to 25 nucleotides in length,
thereby inhibiting Serpina1 expression in the cell.