US 12,247,203 B2
Modified RNA agents with reduced off-target effect
Shigeo Matsuda, Cambridge, MA (US); Mark K. Schlegel, Cambridge, MA (US); Maja Janas, Cambridge, MA (US); Vasant R. Jadhav, Cambridge, MA (US); Martin Maier, Cambridge, MA (US); Klaus Charisse, Cambridge, MA (US); Muthiah Manoharan, Cambridge, MA (US); Kallanthottathil Rajeev, Cambridge, MA (US); and Jayaprakash K. Nair, Cambridge, MA (US)
Assigned to Alnylam Pharmaceuticals, Inc.
Appl. No. 17/055,710
Filed by Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
PCT Filed May 16, 2019, PCT No. PCT/US2019/032633
§ 371(c)(1), (2) Date Nov. 16, 2020,
PCT Pub. No. WO2019/222479, PCT Pub. Date Nov. 21, 2019.
Claims priority of provisional application 62/719,291, filed on Aug. 17, 2018.
Claims priority of provisional application 62/672,405, filed on May 16, 2018.
Prior Publication US 2021/0238595 A1, Aug. 5, 2021
Int. Cl. C07H 21/04 (2006.01); C12N 15/113 (2010.01)
CPC C12N 15/113 (2013.01) [C12N 2310/14 (2013.01); C12N 2310/318 (2013.01); C12N 2310/323 (2013.01); C12N 2310/33 (2013.01); C12N 2310/344 (2013.01); C12N 2310/53 (2013.01)] 20 Claims
 
1. A double-stranded RNA (dsRNA) molecule capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 40 nucleotides, wherein the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference, wherein said antisense strand comprises one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5′ region, counting from the 5′-end of the antisense strand, wherein the destabilizing modification is a Modified Unlocked Nucleic Acid (mUNA), and wherein (i) said sense strand comprises an ASGPR ligand; or (ii) the dsRNA has a melting temperature of from about 40° C. to about 80° C.