Search

JP-2026076154-A - Ketohexokinase (KHK) iRNA composition and method of use thereof

JP2026076154AJP 2026076154 AJP2026076154 AJP 2026076154AJP-2026076154-A

Abstract

[Problem] To provide a composition for treating diseases, disorders, and symptoms related to ketohexokinase (KHK) activity. [Solution] The present invention provides RNAi agents, such as dsRNA agents, that target the ketohexokinase (KHK) gene. The present invention also provides a method of using an RNAi agent to inhibit KHK gene expression in a target, and a method for treating or preventing KHK-related diseases. [Selection Diagram] None

Inventors

  • グレゴリー・ヒンクル

Assignees

  • アルナイラム ファーマシューティカルズ， インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20251224
Priority Date
20180918

Claims (20)

  1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of the ketohexokinase (KHK) gene, wherein the dsRNA agent comprises a sense strand and an antisense strand, the sense strand comprising nucleotides 89-107, 176-194, 264-282, 474-492, 508-526, 529-547, 562-580, 616-646, 682-700, 705-723, 705-757, 705-799, 739-757, 739-799, 760-799, 804-822, 837-855, 892-910 of Sequence ID No. 1. A double-stranded ribonucleic acid (dsRNA) agent comprising at least 15 consecutive nucleotides differing by three or fewer nucleotides from one of the following nucleotide sequences: 959-977, 992-1010, 922-1041, 1013-1041, 1069-1108, 1169-1140, 1111-1140, 1155-1196, 1221-1261, 1267-1294, or 1320-1350, wherein the antisense strand comprises at least 15 consecutive nucleotides differing by three or fewer nucleotides from the nucleotide sequence of SEQ ID NO: 2.
  2. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of the ketohexokinase (KHK) gene, wherein the dsRNA comprises a sense strand and an antisense strand, and the antisense strand includes a complementary region containing at least 15 consecutive nucleotides that differ from one of the antisense sequences listed in Table 3 or 5 by three or fewer nucleotides.
  3. The antisense chains are AD-72506, AD-72319, AD-72502, AD-72513, AD-72499, AD-72303, AD-72500, AD-72522, AD-72512, AD-72304, AD-72514, AD-72257, AD-72295, AD-72332, AD-72507, AD-72311, AD-72501, AD-72508, AD-72293, AD-72322, AD-72264, AD-72290, A The dsRNA agent according to claim 2, comprising at least 15 consecutive nucleotides that differ by three or fewer nucleotides from any one double-stranded antisense sequence selected from the group consisting of D-72338, AD-72315, AD-72272, AD-72337, AD-72298, AD-72503, AD-72327, AD-72521, AD-72309, AD-72313, AD-72517, AD-72316, AD-72335, or AD-72317.
  4. A dsRNA agent according to any one of claims 1 to 3, wherein the sense and antisense strands comprise sequences selected from either of the sequences in Table 3 or 5.
  5. A dsRNA agent according to any one of claims 1 to 4, wherein the dsRNA comprises at least one modified nucleotide.
  6. A dsRNA agent according to any one of claims 1 to 4, wherein all nucleotides of the sense strand and all nucleotides of the antisense strand are modified.
  7. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of the ketohexokinase (KHK) gene, wherein the dsRNA agent includes a sense strand and an antisense strand that form a double-stranded region. The sense strand consists of nucleotides 89-107, 176-194, 264-282, 474-492, 508-526, 529-547, 562-580, 616-646, 682-700, 705-723, 705-757, 705-799, 739-757, 739-799, 760-799, 804-822, 837-855, 892-910, 959-977, 992-1010, 922-1041, 1013- The antisense strand comprises at least 15 consecutive nucleotides that differ by three or fewer nucleotides from one of the nucleotide sequences 1041, 1069-1108, 1169-1140, 1111-1140, 1155-1196, 1221-1261, 1267-1294, or 1320-1350, and the antisense strand comprises at least 15 consecutive nucleotides that differ by three or fewer nucleotides from the nucleotide sequence of SEQ ID NO: 2, Substantially all nucleotides of the sense strand and substantially all nucleotides of the antisense strand are modified nucleotides. The sense chain is conjugated to a ligand bound to its 3' end. Double-stranded ribonucleic acid (dsRNA) agent.
  8. The dsRNA agent according to claim 7, wherein all nucleotides of the sense strand and all nucleotides of the antisense strand contain modifications.
  9. The dsRNA agent according to claim 7, wherein at least one modified nucleotide is selected from the group consisting of deoxy-nucleotides, 3'-terminal deoxythymine (dT) nucleotides, 2'-O-methyl-modified nucleotides, 2'-fluoro-modified nucleotides, 2'-deoxy-modified nucleotides, locked nucleotides, unlocked nucleotides, conformationally constrained nucleotides, constrained ethyl nucleotides, non-basic nucleotides, 2'-amino-modified nucleotides, 2'-O-allyl-modified nucleotides, 2'-C-alkyl-modified nucleotides, 2'-hydroxyl-modified nucleotides, 2'-methoxyethyl-modified nucleotides, 2'-O-alkyl-modified nucleotides, morpholino nucleotides, phosphoramidates, nucleotides containing unnatural bases, tetrahydropyran-modified nucleotides, 1,5-anhydrohexitol-modified nucleotides, cyclohexenyl-modified nucleotides, nucleotides containing a phosphorothioate group, nucleotides containing a methylphosphonate group, nucleotides containing a 5'-phosphate, and nucleotides containing a 5'-phosphate mimetic.
  10. The dsRNA agent according to claim 9, wherein the modified nucleotide contains a short sequence of the 3' terminal deoxythymine nucleotide (dT).
  11. The dsRNA agent according to claim 2 or 3, wherein the complementary region has a length of at least 17 nucleotides.
  12. The dsRNA agent according to claim 2 or 3, wherein the complementary region has a nucleotide length of 19 to 21 nucleotides.
  13. The dsRNA agent according to claim 12, wherein the complementary region has a length of 19 nucleotides.
  14. A dsRNA agent according to any one of claims 1 to 3 and 7, wherein each chain has a length of 30 nucleotides or less.
  15. A dsRNA agent according to any one of claims 1 to 3 and 7, wherein at least one strand comprises a 3' overhang of at least one nucleotide.
  16. A dsRNA agent according to any one of claims 1 to 3 and 7, wherein at least one strand comprises 3' overhangs of at least two nucleotides.
  17. A dsRNA agent according to any one of claims 1 to 3, further comprising a ligand.
  18. The dsRNA agent according to claim 17, wherein the ligand is conjugated to the 3' end of the sense strand of the dsRNA agent.
  19. The dsRNA agent according to claim 7 or 17, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
  20. The ligand is The dsRNA agent according to claim 19.

Description

(Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 62/732,600, filed on 18 September 2018, which is incorporated herein by reference in its entirety. Sequence Listing The present invention includes a sequence listing submitted in electronic format in ASCII format, which is incorporated herein by reference in its entirety. A copy of the said ASCII file was created on 13 September 2019, named 121301-06020_SL.txt, and is 309,325 bytes in size. Epidemiological studies have shown that Western diets are one of the main causes of the modern obesity epidemic. Increased fructose intake is associated with the use of high-nutrient soft drinks and processed foods and is considered a major factor in the obesity epidemic. High-fructose corn syrup began to be widely used in the food industry by 1967. Although glucose and fructose have the same calorie value per molecule, these two sugars are metabolized via different metabolic pathways and utilize different GLUT transporters. Unlike the glucose metabolic pathway, fructose is almost exclusively metabolized in the liver, and the fructose metabolic pathway is not regulated by feedback inhibition by its products (Khaitan Z et al., (2013) J. Nutr. Metab. 2013, Article ID 682673, 1-12). Hexokinases and phosphofructokinases (PFKs) regulate the production of glyceraldehyde-3-P from glucose, while fructokinases or ketohexokinases (KHKs), which are responsible for the phosphorylation of fructose to fructose-1-phosphate in the liver, are not downregulated even when the concentration of fructose-1-phosphate increases. As a result, all fructose entering the cell is rapidly phosphorylated (Khaitan Z et al., (2013) J. Nutr. Metab. 2013, Article ID 682673, 1-12). The continuous use of ATP to phosphorylate fructose to fructose-1-phosphate leads to intracellular phosphate depletion, ATP depletion, activation of AMP deaminase, and uric acid formation (Khaitan Z. et al., (2013) J. Nutr. Metab. Article ID 682673, 1-12). Increased uric acid further promotes the upregulation of KHK (Lanaspa M.A. et al., (2012) PLOS ONE 7(10):1-11), leading to endothelial and adipocyte dysfunction. Subsequently, fructose-1-phosphate is converted to glyceraldehyde by aldolase B and phosphorylated to glyceraldehyde-3-phosphate. The latter proceeds to the downstream glycolysis pathway, forming pyruvate and entering the citrate cycle. From there, under sufficient supply conditions, citrate is transported from the mitochondria to the cytosol, providing acetylcoenzyme A for lipid synthesis (Figure 1). Phosphorylation of fructose by KHK, followed by activation of lipid synthesis, can lead to conditions such as fatty liver, hypertriglyceridemia, dyslipidemia, and insulin resistance. Inflammatory changes in renal proximal tubular cells have also been shown to be induced by KHK activity (Cirillo P. et al., (2009) J. Am. Soc. Nephrol. 20: 545-553). Phosphorylation of fructose by KHK is associated with liver diseases (e.g., fatty liver, steatohepatitis), dyslipidemia (e.g., hyperlipidemia, high LDL cholesterol, low HDL cholesterol, hypertriglyceridemia, postprandial hypertriglyceridemia), impaired glycemic control (e.g., insulin resistance, type II diabetes), cardiovascular diseases (e.g., hypertension, endothelial cell dysfunction, etc.), kidney diseases (e.g., acute kidney injury, tubular dysfunction, proximal tubular inflammatory changes, chronic kidney disease, etc.), metabolic syndrome, adipocyte dysfunction, visceral fat deposition, obesity, hyperuricemia, gout, eating disorders, and excessive sugar cravings. Therefore, compositions and methods for treating diseases, disorders, and symptoms associated with KHK activity are needed in the art. (Summary of the invention) The present invention provides compositions comprising RNAi agents, such as double-stranded RNAi agents, that target ketohexokinase (KHK). The present invention also provides methods of using the compositions of the present invention to treat subjects with diseases that benefit from inhibiting KHK expression or reducing the expression of the KHK gene, such as liver diseases (e.g., fatty liver, steatohepatitis, especially non-alcoholic steatohepatitis (NASH)), dyslipidemia (e.g., hyperlipidemia, high LDL cholesterol, low HDL cholesterol, hypertriglyceridemia, postprandial hypertriglyceridemia), impaired glycemic control (e.g., insulin resistance, type II diabetes, etc.), cardiovascular diseases (e.g., hypertension, endothelial cell dysfunction), kidney diseases (e.g., acute kidney injury, tubular dysfunction, inflammatory changes in the proximal tubules, chronic kidney disease), metabolic syndrome, adipocyte dysfunction, visceral fat deposition, obesity, hyperuricemia, gout, eating disorders, and excessive sugar cravings. In one aspect, the present invention provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of ketohexokinase (KHK), wherein the dsRNA comprises