JP-2022532652-A5 -

Dates

Publication Date

20230509

Application Date

20200515

Description

References All publications and patents referenced herein, including those listed below, are incorporated herein by reference in their entirety, as if each individual publication or patent were specifically and individually incorporated by reference. In case of any conflict, the present application, including any definitions herein, shall prevail. Finally, preferred embodiments of the present invention are described in separate sections. [Embodiment 1] A method for reducing or inhibiting the expression of a target gene in a subject, To the aforementioned target that requires it, a) Double-stranded iRNA agents containing the following: An antisense strand complementary to the aforementioned target gene; A sense chain complementary to the aforementioned antisense chain; 2'-OMe modifications to nucleotides greater than 15, greater than 20, greater than 25, or greater than 30; and Optionally, a carbohydrate ligand conjugated to at least one of the chains via a linker or carrier, and b) Penetration enhancer A method comprising the step of orally administering a formulation containing the above. [Embodiment 2] The method according to Embodiment 1, wherein the double-stranded iRNA agent is administered at a dose of approximately 50 mg or less per kg of body weight. [Embodiment 3] The method according to Embodiment 2, wherein the double-stranded iRNA agent is administered at a dose of approximately 1 to approximately 30 mg/kg body weight. [Embodiment 4] The method according to Embodiment 3, wherein the double-stranded iRNA agent is administered at a dose of approximately 3 to approximately 25 mg/kg body weight. [Embodiment 5] The method according to Embodiment 1, wherein the concentration of the penetration enhancer in the formulation is approximately 200 mM or less. [Embodiment 6] The method according to Embodiment 5, wherein the concentration of the penetration enhancer in the formulation is approximately 150 mM or less. [Embodiment 7] The method according to Embodiment 1, wherein the formulation is administered in a single dose. [Embodiment 8] The method according to Embodiment 1, wherein the formulation is administered in multiple doses. [Embodiment 9] The method according to Embodiment 1, wherein the sense strand and the antisense strand are each 15 to 30 nucleotides long. [Embodiment 10] The method according to Embodiment 9, wherein the sense strand and the antisense strand are each 21 to 23 nucleotides long. [Method 11] The method according to Embodiment 9, wherein the double-stranded iRNA agent includes a single-stranded overhang of 1, 2, or 3 nucleotides in length at at least one of its terminals. [Embodiment 12] The method according to Embodiment 11, wherein the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long, and the strands form a double-stranded region of 21 consecutive base pairs having a single-stranded overhang of 2 nucleotides long at the 3' end. [Embodiment 13] The method according to Embodiment 1, wherein the double-stranded iRNA agent comprises a phosphate mimetic selected from the group consisting of 5'-phosphodithioate (5'-PS2 ) , 5'-vinylphosphonate (5'-VP), 5'-methylphosphonate (5'-MePhos), and 5'-deoxy-5'-C-malonyl at the 5' end of the strand. [Embodiment 14] The method according to Embodiment 13, wherein the phosphate mimetic is 5'-vinylphosphonate (5'-VP). [Embodiment 15] The method according to Embodiment 13, wherein the phosphate mimetic is located at the 5' end of the antisense chain. [Embodiment 16] The method according to Embodiment 1, wherein the double-stranded iRNA agent comprises at least two blocks of modification of the internucleotide bond of two consecutive phosphorothioates or methylphosphonates. [Embodiment 17] The method according to Embodiment 16, wherein the antisense strand includes at least two consecutive phosphorothioate nucleotide linkage modifications within positions 18 to 23 of the antisense strand, counting from the 5' end of the antisense strand; and the sense strand includes at least two consecutive phosphorothioate nucleotide linkage modifications within positions 1 to 5 of the sense strand, counting from the 5' end of the sense strand. [Embodiment 18] The method according to Embodiment 1, wherein the double-stranded iRNA agent contains a 2'-F modification of less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, or less than 3. [Embodiment 19] The method according to Embodiment 1, wherein the sense strand includes a 2'-F modification at positions 7 and 9-11, counting from the 5' end of the sense strand. [Embodiment 20] The method according to Embodiment 1, wherein the antisense chain includes a 2'-F modification at positions 2, 6, 14, and 16, counting from the 5' end of the antisense chain; or at positions 2, 6, 8-9, 14, and 16, counting from the 5' end of the antisense chain. [Embodiment 21] The method according to Embodiment 1, wherein the carbohydrate liga