CTGF gene-specific double-stranded oligonucleotide, and a composition for preventing and treating fibrotic diseases and respiratory-related diseases comprising same
The present invention relates to a double-stranded oligonucleotide capable of inhibiting CTGF expression with a very specific and high efficiency, a double-stranded oligonucleotide structure and nanoparticles comprising the double-stranded oligonucleotide, and a use thereof in preventing or treating of fibrotic or respiratory diseases.
1 . A connective growth tissue factor (CTGF)-specific double-stranded oligonucleotide construct for inducing RNAi via siRNA or shRNA, having a structure of Structural Formula (1) below:
A-X—R—Y—B Structural Formula (1)
wherein in Structural Formula 1, A is a hydrophilic material, B is a hydrophobic material, X and Y are each independently a simple covalent bond or a linker-mediated covalent bond, and R is a double-stranded oligonucleotide for inducing RNAi via siRNA or shRNA, said double-stranded oligonucleotide comprising a sense strand consisting of the sequence of SEQ ID NO: 10 and an antisense strand comprising a sequence complementary thereto, wherein the sense strand is DNA, and the antisense strand is RNA.
2 . The CTGF-specific double-stranded oligonucleotide construct according to claim 1 , having a structure of Structural Formula (2) below:
in Structural Formula (2), S and AS are a sense strand and an antisense strand of the double-stranded oligonucleotide according to claim 1 , respectively, and A, B, X, and Y are as defined in claim 1 .
3 . The CTGF-specific double-stranded oligonucleotide construct according to claim 2 , having a structure of Structural Formula (3) or Structural Formula (4) below:
in Structural Formulas (3) and (4), A, B, X, Y, S, and AS are as defined in claim 2 , and 5′ and 3′ are 5′ and 3′ ends of the sense strand of the double-stranded oligonucleotide.
4 . The CTGF-specific double-stranded oligonucleotide construct according to claim 1 , wherein the hydrophilic material has a structure of Structural Formula (5) or Structural Formula (6) below:
(A′ m -J) n Structural Formula (5)
(J-A′ m ) n Structural Formula (6)
in Structural Formula (5) or Structural Formula (6), A′ is a hydrophilic material monomer, J is a linker connecting m hydrophilic material monomers to each other or connecting m hydrophilic material monomers and a double-stranded oligonucleotide to each other, m is an integer of 1 to 15, n is an integer of 1 to 10, the hydrophilic material monomer A′ is any one compound selected from among compounds (1) to (3) below, and the linker (J) is selected from the group consisting of —PO 3 —, —SO 3 —, and —CO 2 —:
in compound (1), G is selected from the group consisting of O, S, and NH;
5 . The CTGF-specific double-stranded oligonucleotide construct according to claim 4 , having a structure of Structural Formula (7) or Structural Formula (8) below:
(A′ m -J) n -X—R—Y—B Structural Formula (7)
(J-A′ m ) n —X—R—Y—B. Structural Formula (8)
6 . Nanoparticles comprising the double-stranded oligonucleotide construct according to claim 1 .
7 . The nanoparticles according to claim 6 , wherein the nanoparticles are configured such that double-stranded oligonucleotide constructs comprising double-stranded oligonucleotides comprising different sequences are mixed.
8 . A method of treating fibrosis or a respiratory disease by inhibiting expression of CTGF, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the CTGF-specific double-stranded oligonucleotide construct according to claim 1 .
9 . A method of preventing or treating fibrosis or a respiratory disease by inhibiting expression of CTGF, in a subject in need thereof, comprising administering to the subject the nanoparticles according to claim 6 as an active ingredient.
10 . The method according to claim 8 , wherein the respiratory disease is any one selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute or chronic bronchitis, allergic rhinitis, productive cough, bronchitis, bronchiolitis, laryngopharyngitis, tonsillitis, and laryngitis.
11 . The method according to claim 8 , wherein the fibrosis is any one selected from the group consisting of idiopathic pulmonary fibrosis (IPF), liver fibrosis, cirrhosis, myelofibrosis, myocardial fibrosis, renal fibrosis, keloid, pulmonary fibrosis, cardiac fibrosis, and radiation-induced fibrosis.
12 . The method according to claim 9 , wherein the respiratory disease is any one selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute and chronic bronchitis, allergic rhinitis, productive cough, bronchitis, bronchiolitis, laryngopharyngitis, tonsillitis, and laryngitis.
13 . The method according to claim 9 , wherein the fibrosis is any one selected from the group consisting of idiopathic pulmonary fibrosis (IPF), liver fibrosis, cirrhosis, myelofibrosis, myocardial fibrosis, renal fibrosis, keloid, pulmonary fibrosis, cardiac fibrosis, and radiation-induced fibrosis.
14 . A method of treating fibrosis or a respiratory disease by inhibiting expression of CTGF, in a subject in need thereof, comprising administering to the subject the CTGF-specific double-stranded oligonucleotide construct according to claim 1 as an active ingredient.
15 . The method according to claim 14 , wherein the respiratory disease is any one selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute and chronic bronchitis, allergic rhinitis, productive cough, bronchitis, bronchiolitis, laryngopharyngitis, tonsillitis, and laryngitis.
16 . The method according to claim 14 , wherein the fibrosis is any one selected from the group consisting of idiopathic pulmonary fibrosis (IPF), liver fibrosis, cirrhosis, myelofibrosis, myocardial fibrosis, renal fibrosis, keloid, pulmonary fibrosis, cardiac fibrosis, and radiation-induced fibrosis.