Hsd17b13-related double stranded oligonucleotide compositions and methods relating thereto

A chirally controlled oligonucleotide composition comprising double stranded oligonucleotides wherein the guide and passenger strands of the double stranded oligonucleotides are independently characterized by:

• a) a common base sequence and length;
• b) a common pattern of backbone linkages;
• and
• c) a common pattern of backbone chiral centers;
• which composition is chirally controlled in that it is enriched, relative to a substantially racemic preparation of guide strands having the same common base sequence and length, for oligonucleotides having a common pattern of chiral centers;
• and
• a) wherein the guide strands are complementary or substantially complementary to an HSD17B13 target RNA sequence, and comprise:
• i. backbone phosphorothioate chiral centers in Sp configuration between the 3′ terminal nucleotide and the penultimate (N-1) nucleotide and as between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide,
• ii. backbone phosphorothioate chiral centers in Rp, Sp, or alternating configurations between the 5′ terminal (+1) nucleotide and the immediately downstream (+2)nucleotide and between the +2 nucleotide and the immediately downstream (+3) nucleotide;
• iii. one or more backbone phosphorothioate chiral centers in Rp or Sp configuration upstream of backbone phosphorothioate chiral centers in Sp configuration between the 3′ terminal nucleotide and the penultimate (N-1) nucleotide and as between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide;
• and/or
• iv. one or more backbone phosphorothioate chiral centers in Rp or Sp configuration between the 5′ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide and between the (+2) nucleotide and the immediately downstream (+3) nucleotide, as well as between one or both of:
• (a) the (+3) nucleotide and the (+4) nucleotide;
• and (b) the (+5) nucleotide and the (+6) nucleotide;
• or
• b) the guide strand comprises one or more Rp, Sp, or stereorandom non-negatively charged internucleotidic linkage occurs between any two adjacent nucleotides between the second (+2) nucleotide relative to the 5′ terminal nucleotide of the guide strand and the penultimate 3′ (N-1) nucleotide of the guide strand, where N is the 3′ terminal nucleotide;
• c) the guide strand comprises a 2′ modification, of the 3′ nucleotide of a nucleotide pair linked by an Rp, Sp, or stereorandom non-negatively charged internucleotidic linkage;
• d) the passenger strands comprise one or both of:
• i. 0-n Rp, Sp, or stereorandom non-negatively charged internucleotidic linkages, where n is about 1 to 49, and
• ii. one or more backbone chiral centers in Rp or Sp configuration,
• e) the guide and passenger strands have a length of about 15 to about 49 nucleotides;
• and
• f) the guide and passenger strands are capable of directing HSD17B13-specific RNA interference.

A method for reducing level and/or activity of an HSD17B13 transcript or a protein encoded thereby, comprising administering to a cell expressing the HSD17B13 transcript a double stranded oligonucleotide, wherein the double stranded oligonucleotide comprises a guide strand and a passenger strand wherein:

• a) the guide strand is complementary or substantially complementary to an HSD17B13 target RNA sequence, and comprises:
• i. backbone phosphorothioate chiral centers in Sp configuration between the 3′ terminal nucleotide and the penultimate (N-1) nucleotide and as between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide,
• ii. backbone phosphorothioate chiral centers in Rp, Sp, or alternating configurations between the 5′ terminal (+1) nucleotide and the immediately downstream (+2)nucleotide and between the +2 nucleotide and the immediately downstream (+3) nucleotide;
• iii. one or more backbone phosphorothioate chiral centers in Rp or Sp configuration upstream of backbone phosphorothioate chiral centers in Sp configuration between the 3′ terminal nucleotide and the penultimate (N-1) nucleotide and as between the penultimate (N-1) nucleotide and the immediately upstream (N-2) nucleotide;
• and/or
• iv. one or more backbone phosphorothioate chiral centers in Rp or Sp configuration between the 5′ terminal (+1) nucleotide and the immediately downstream (+2) nucleotide and between the (+2) nucleotide and the immediately downstream (+3) nucleotide, as well as between one or both of:
• (a) the (+3) nucleotide and the (+4) nucleotide;
• and (b) the (+5) nucleotide and the (+6) nucleotide;
• b) the guide strand comprises one or more Rp, Sp, or stereorandom non-negatively charged internucleotidic linkage occurs between any two adjacent nucleotides between the second (+2) nucleotide relative to the 5′ terminal nucleotide of the guide strand and the penultimate 3′ (N-1) nucleotide of the guide strand, where N is the 3′ terminal nucleotide;
• c) the guide strand comprises a 2′ modification, of the 3′ nucleotide of a nucleotide pair linked by an Rp, Sp, or stereorandom non-negatively charged internucleotidic linkage;
• d) the passenger strand comprises one or both of:
• i. 0-n Rp, Sp, or stereorandom non-negatively charged internucleotidic linkages, where n is about 1 to 49, and
• ii. one or more backbone chiral centers in Rp or Sp configuration,
• e) each strand of the dsRNAi agent independently has a length of about 15 to about 49 nucleotides,
• f) the dsRNAi is capable of directing HSD17B13-specific RNA interference;
• wherein the guide strand of double stranded oligonucleotide comprises a HSD17B13-binding sequence that is completely complementary to an HSD17B13 target sequence in the transcript.