Compositions Containing Oligonucleotides and Their Use

Abstract

Compounds comprising oligonucleotide molecules conjugated to ligands for glucose transporters (GLUT) for the regulation of target molecules, compositions comprising the same, and methods of using the compositions are provided herein.

Description

Cross - reference to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 432,531, filed on December 14, 2022, and Korean Patent Application No. 10 - 2022 - 0062663, filed on May 23, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] Sequence listing This application includes a sequence listing having 245 sequences. Background

[0003] The development of innovative treatment strategies for the treatment of brain disorders and cancer has always been the subject of intense research and exploration. In recent years, RNA interference (RNAi) has emerged as a promising therapeutic approach, particularly through the use of small interfering RNA (siRNA) and SAMiRNA (trademark) technologies.

[0004] However, the successful clinical application of therapeutic agents has been hampered by issues related to the efficient and targeted delivery of RNAi molecules to specific tissues and cells, particularly the brain. The blood - brain barrier (BBB), a highly selective barrier that separates the central nervous system (CNS) from the systemic circulation, poses a major obstacle to the delivery of therapeutic agents to the brain. Furthermore, in the case of cancer, effectively delivering RNAi molecules to tumor cells while minimizing off - target effects is a significant challenge.

[0005] Therefore, the development of an efficient delivery system that can overcome these barriers and provide targeted delivery to the brain and tumor cells holds great therapeutic potential. Such a system would enhance the effectiveness and specificity of RNAi - based therapies and lead to improved treatment outcomes for patients with brain disorders and cancer.

Technical field

[0006] The present disclosure relates to compounds comprising oligonucleotide molecules and compositions containing the same, methods for preventing or treating disorders, methods for alleviating or delaying one or more signs or symptoms of a disorder, methods for targeted delivery of a compound, methods for reducing or inhibiting the expression and / or activity of a target molecule in a particular tissue, organ, or cell, and methods for increasing the blood-brain barrier permeability of a compound. Overview

[0007] In one aspect, Formula 16: A-X-R-Y-B Formula 16 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A compound comprising the structure of, A ligand molecule or a functional analog thereof for a glucose transporter (GLUT) is covalently linked to the terminus of A, the terminus of B, or a combination thereof, and R regulates the expression level and / or activity level of a target molecule, is provided herein.

[0008] In some embodiments, a ligand molecule or a functional analog thereof for a glucose transporter (GLUT) is covalently linked to the terminus of A, the terminus of B, or a combination thereof via a second linker.

[0009] In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-.

[0010] In some embodiments, a ligand molecule of a glucose transporter (GLUT) or a functional analog thereof is covalently linked to the terminus of A. In some embodiments, a ligand molecule of a glucose transporter (GLUT) or a functional analog thereof is covalently linked to the terminus of B. In some embodiments, a ligand molecule of a glucose transporter (GLUT) or a functional analog thereof is covalently linked to the termini of both A and B.

[0011] In some embodiments, the present disclosure provides a compound of formula 16: A-X-R-Y-B Formula 16 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) and a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker to the terminus of A, the terminus of B, or a combination thereof, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, and R provides a compound that regulates the expression level and / or activity level of a target molecule.

[0012] In some embodiments, the compound is of formula 14 or formula 15: (L i )-A-X-R-Y-B Formula 14, A-X-R-Y-B-(L j ) Formula 15 (wherein L is a ligand molecule for GLUT or a functional analog thereof, i and j are independently integers from 0 to 10, When i is 0, j is an integer from 1 to 10, and when j is 0, i is an integer from 1 to 10) includes the structure of

[0013] In some embodiments, the ligand molecule for GLUT is a sugar.

[0014] In some embodiments, the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose.

[0015] In some embodiments, the ligand molecule for GLUT is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, trehalose, and urate.

[0016] In some embodiments, GLUT is selected from the group consisting of GLUT1 to GLUT14.

[0017] In some embodiments, the ligand molecule for GLUT is fructose, and GLUT is selected from the group consisting of GLUT2, GLUT5, GLUT7, GLUT8, GLUT9, GLUT11, and GLUT12.

[0018] In some embodiments, the ligand molecule for GLUT is galactose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, and GLUT14.

[0019] In some embodiments, the ligand molecule for GLUT is glucose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, and GLUT12.

[0020] In some embodiments, the ligand molecule for GLUT is mannose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4.

[0021] In some embodiments, the ligand molecule for GLUT is xylose, and GLUT is GLUT3.

[0022] In some embodiments, the ligand molecule for GLUT is dehydroascorbic acid, and GLUT is GLUT4.

[0023] In some embodiments, the ligand molecule for GLUT is trehalose, and GLUT is GLUT8.

[0024] In some embodiments, the ligand molecule for GLUT is uric acid, and GLUT is GLUT9.

[0025] In some embodiments, R is a double-stranded oligonucleotide molecule or a single-stranded oligonucleotide molecule.

[0026] In some embodiments, R is an inhibitory oligonucleotide molecule.

[0027] In some embodiments, the inhibitory oligonucleotide molecule reduces or inhibits the expression and / or activity of the target molecule.

[0028] In some embodiments, the target molecule is any one selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA. Specifically, the target molecule can be an mRNA transcript of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, or RhoA.

[0029] In some embodiments, the inhibitory oligonucleotide molecule is siRNA, shRNA, miRNA, amiRNA, an antisense oligonucleotide molecule, an RNAi agent, or any combination thereof.

[0030] In some embodiments, R is a double-stranded oligonucleotide molecule comprising a sense strand and an antisense strand comprising a sequence complementary to the sense strand.

[0031] In some embodiments, the sense strand or the antisense strand is 19 to 31 nucleotides in length.

[0032] In some embodiments, at least one phosphate group is linked to the 5' end of the antisense strand.

[0033] In some embodiments, the compound has the formula 2: A-X-S-Y-B AS Formula 2 (wherein S is the sense strand and AS is the antisense strand) includes the structure of

[0034] In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 50 oligonucleotides, 10 to 40 oligonucleotides, or 15 to 30 oligonucleotides.

[0035] In some embodiments, R is DNA, RNA, or a combination thereof. In some embodiments, R is a double-stranded oligonucleotide comprising a sequence in the form of an RNA / RNA, DNA / DNA, or DNA / RNA hybrid.

[0036] In some embodiments, R includes backbone modifications including phosphorothioate linkages, phosphorodiamidate linkages, boranophosphate linkages, methylphosphonate linkages, or any combination thereof.

[0037] In some embodiments, R includes locked nucleic acids, peptide nucleic acids, unlocked nucleic acids, or any combination thereof.

[0038] In some embodiments, R includes a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, a 2'-methyl moiety, a 2'-methoxyl moiety, a 2'-amine moiety, a 2'-O-propyl moiety, a 2'-O-2-methylthioethyl moiety, a 2'-O-3-aminopropyl moiety, a 2'-O-3-dimethylaminopropyl moiety, a 2'-O-N-methylacetamino moiety, or a 2'-O-dimethylamidooxyethyl moiety.

[0039] In some embodiments, R includes a modified sugar moiety.

[0040] In some embodiments, the hydrophilic moiety is any one selected from the group consisting of polyethylene glycol (PEG), HEG (hexaethylene glycol), polyvinylpyrrolidone, and polyoxazoline. In some embodiments, the hydrophilic moiety is HEG (hexaethylene glycol). In some embodiments, the hydrophilic moiety comprises or consists of hexaethylene glycol-(-PO3 - hexaethylene glycol)3.

[0041] In some embodiments, the compound has the formula 7 or formula 8: (A’ m -J) n -X-R-Y-B Formula 7, (J-A’ m ) n -X-R-Y-B Formula 8 (wherein, A’ is a monomeric hydrophilic moiety, J is selected from the group consisting of PO3 - , SO3 - and CO2 - and either links A’ to each other or links A’ to X, m is an integer from 1 to 15, n is an integer from 1 to 10, A’ is any one selected from the group consisting of Compound 1, Compound 2, and Compound 3

Chemical formula

Chemical formula

Chemical formula

[0042] ​ In some embodiments, the molecular weight of the hydrophilic moiety is from 200 to 10,000.

[0043] In some embodiments, the hydrophobic moiety is any one selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycol, unsaturated or saturated C 12 ~C 50 , diacyl phosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols, and tocotrienols.

[0044] In some embodiments, the steroid derivative is any one selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cotestanyl formate, and cholestanyl amine.

[0045] In some embodiments, the glyceride derivative is any one selected from the group consisting of monoglycerides, diglycerides, and triglycerides.

[0046] In some embodiments, the molecular weight of the hydrophobic moiety is from 250 to 1,000.

[0047] In some embodiments, X and Y are independently non-cleavable bonds or cleavable bonds.

[0048] In some embodiments, the non-cleavable bond is an amide bond or a phosphorylation bond.

[0049] In some embodiments, the cleavable bond is any one selected from the group consisting of disulfide bonds, acid-cleavable bonds, ester bonds, anhydride bonds, biodegradable bonds, and enzyme-cleavable bonds.

[0050] In another aspect, nanoparticles comprising the compounds provided herein are provided herein.

[0051] In another aspect, provided herein is a composition comprising a compound provided herein or a nanoparticle provided herein.

[0052] In another aspect, provided herein is a pharmaceutical composition comprising a compound provided herein, a nanoparticle provided herein, or a composition provided herein, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0053] In another aspect, provided herein is a method of preventing or treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, wherein the disorder is associated with the expression and / or activity of one or more pathogenic genes, wherein the target molecule is one or more pathogenic genes, wherein the administration reduces or inhibits the expression and / or activity of the target molecule in the subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, thereby alleviating or delaying one or more signs or symptoms of the disorder in the subject as compared to the subject before or without administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0054] In another aspect, provided herein is a method of alleviating or delaying one or more signs or symptoms of a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, wherein the disorder is associated with the expression and / or activity of one or more pathogenic genes, wherein the target molecule is one or more pathogenic genes, Administration reduces or inhibits the expression and / or activity of a target molecule in a subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of a compound, nanoparticle, composition, or pharmaceutical composition provided herein.

[0055] In another aspect, a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) comprising a compound having the structure of, a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, the disorder is related to the expression and / or activity of one or more pathogenic genes, the target molecule is one or more pathogenic genes, administration reduces or inhibits the expression and / or activity of the target molecule in the subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound, thereby alleviating or delaying one or more signs or symptoms of the disorder in the subject as compared to the subject before or without administration of the compound, is provided herein.

[0056] A method of alleviating or delaying one or more signs or symptoms of a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are, independently, a covalent bond or a first linker) comprising administering a compound comprising the structure of, wherein a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, wherein the administering reduces or inhibits the expression and / or activity of a target molecule in a subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound, thereby alleviating or delaying one or more signs or symptoms of a disorder in the subject as compared to the subject before or without administration of the compound.

[0057] In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical formula

Chemical formula

[0058] In some embodiments, the compound is of Formula 18 or Formula 19: (L i )-A-X-R-Y-B Formula 18, A-X-R-Y-B-(L j ) Formula 19 (wherein L is a ligand molecule for GLUT or a functional analog thereof, i and j are, independently, integers from 0 to 10, When i is 0, j is an integer from 1 to 10, and when j is 0, i is an integer from 1 to 10) includes the structure of

[0059] In some embodiments, the ligand molecule for GLUT is a sugar.

[0060] In some embodiments, the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose.

[0061] In some embodiments, the ligand molecule for GLUT is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, trehalose, and urate.

[0062] In some embodiments, GLUT is selected from the group consisting of GLUT1 to GLUT14.

[0063] In some embodiments, the ligand molecule for GLUT is fructose, and GLUT is selected from the group consisting of GLUT2, GLUT5, GLUT7, GLUT8, GLUT9, GLUT11, and GLUT12.

[0064] In some embodiments, the ligand molecule for GLUT is galactose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, and GLUT14.

[0065] In some embodiments, the ligand molecule for GLUT is glucose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, and GLUT12.

[0066] In some embodiments, the ligand molecule for GLUT is mannose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4.

[0067] In some embodiments, the ligand molecule for GLUT is xylose, and GLUT is GLUT3.

[0068] In some embodiments, the ligand molecule for GLUT is dehydroascorbic acid, and GLUT is GLUT4.

[0069] In some embodiments, the ligand molecule for GLUT is trehalose, and GLUT is GLUT8.

[0070] In some embodiments, the ligand molecule for GLUT is uric acid, and GLUT is GLUT9.

[0071] In some embodiments, R is a double-stranded oligonucleotide molecule or a single-stranded oligonucleotide molecule.

[0072] In some embodiments, R reduces or inhibits the expression and / or activity of the target molecule.

[0073] In some embodiments, the target molecule is any one selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA.

[0074] In some embodiments, the inhibitory oligonucleotide molecule is siRNA, shRNA, miRNA, amiRNA, an antisense oligonucleotide molecule, an RNAi agent, or any combination thereof.

[0075] In some embodiments, R is a double-stranded oligonucleotide molecule comprising a sense strand and an antisense strand comprising a sequence complementary to the sense strand.

[0076] In some embodiments, the sense strand or the antisense strand is 19 to 31 nucleotides in length.

[0077] In some embodiments, at least one phosphate group is linked to the 5' end of the antisense strand.

[0078] In some embodiments, the compound has the formula 2: A-X-S-Y-B AS Formula 2 (wherein S is the sense strand and AS is the antisense strand) and includes the structure of.

[0079] In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 50 oligonucleotides, 10 to 40 oligonucleotides, or 15 to 30 oligonucleotides.

[0080] In some embodiments, R is DNA, RNA, or a combination thereof.

[0081] In some embodiments, R includes backbone modifications including phosphorothioate linkages, phosphorodiamidate linkages, boranophosphate linkages, methylphosphonate linkages, or any combination thereof.

[0082] In some embodiments, R includes locked nucleic acids, peptide nucleic acids, unlocked nucleic acids, or any combination thereof.

[0083] In some embodiments, R comprises a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, a 2'-methyl moiety, a 2'-methoxyl moiety, a 2'-amine moiety, a 2'-O-propyl moiety, a 2'-O-2-methylthioethyl moiety, a 2'-O-3-aminopropyl moiety, a 2'-O-3-dimethylaminopropyl moiety, a 2'-O-N-methylacetamido moiety or a 2'-O-dimethylamidooxyethyl moiety.

[0084] In some embodiments, R comprises a modified sugar moiety.

[0085] In some embodiments, the hydrophilic moiety is any one selected from the group consisting of polyethylene glycol (PEG), polyvinyl pyrrolidone and polyoxazoline.

[0086] In some embodiments, the compound has the formula 7 or formula 8: (A’ m -J) n -X-R-Y-B Formula 7, (J-A’ m ) n -X-R-Y-B Formula 8 (wherein, A’ is a monomeric hydrophilic moiety, J is selected from the group consisting of PO3 - , SO3 - and CO2 - and either links A’ to each other or links A’ to X, m is an integer from 1 to 15, n is an integer from 1 to 10, A’ is Compound 1, Compound 2 and Compound 3

Chemical formula

Chemical formula

[0087] In some embodiments, the molecular weight of the hydrophilic moiety is from 200 to 10,000.

[0088] In some embodiments, the hydrophobic moiety is any one selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycols, unsaturated or saturated C 12 ~C 50 , diacyl phosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols, and tocotrienols.

[0089] In some embodiments, the steroid derivative is any one selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cotestanyl formate, and cholestanyl amine.

[0090] In some embodiments, the glyceride derivative is any one selected from the group consisting of monoglycerides, diglycerides, and triglycerides.

[0091] In some embodiments, the molecular weight of the hydrophobic moiety is from 250 to 1,000.

[0092] In some embodiments, X and Y are independently non-cleavable bonds or cleavable bonds.

[0093] In some embodiments, the non-cleavable bond is an amide bond or a phosphorylation bond.

[0094] In some embodiments, the cleavable bond is any one selected from the group consisting of a disulfide bond, an acid-cleavable bond, an ester bond, an anhydride bond, a biodegradable bond, and an enzyme-cleavable bond.

[0095] In some embodiments, the compound is formulated as nanoparticles.

[0096] In some embodiments, the compound is formulated as a composition.

[0097] In some embodiments, the composition is formulated as a pharmaceutical composition, and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0098] In some embodiments, the disorder is a neuropathy.

[0099] In some embodiments, the neuropathy is Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman syndrome, Rett syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury.

[0100] In some embodiments, the disorder is Alzheimer's disease, and the target molecule is BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, or any combination thereof.

[0101] In some embodiments, the disorder is Parkinson's disease, and the target molecule is α-synuclein.

[0102] In some embodiments, the disorder is Huntington's disease, and the target molecule is huntingtin (Htt).

[0103] In some embodiments, the disorder is multiple sclerosis and the target molecule is Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, or any combination thereof.

[0104] In some embodiments, the disorder is spinal cord injury and the target molecule is glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, RhoA, or any combination thereof.

[0105] In some embodiments, the disorder is cancer.

[0106] In some embodiments, the cancer is brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, gastric cancer, colorectal cancer, or any combination thereof.

[0107] In some embodiments, the cancer is glioblastoma, non-small cell lung cancer, prostate cancer, pancreatic ductal adenocarcinoma, metastatic gastric adenocarcinoma, invasive ductal carcinoma of the breast, or colorectal cancer.

[0108] In some embodiments, one or more signs or symptoms include Aβ peptide accumulation in the brain, tau peptide accumulation in the brain, phosphorylated tau accumulation in the brain, tau protein phosphorylation, hippocampal damage, cognitive deficits, or any combination thereof.

[0109] In some embodiments, the Aβ peptide accumulation occurs in the CA1 and uncus of the subject's brain.

[0110] In some embodiments, the tau peptide accumulation occurs in the CA1 and uncus of the subject's brain.

[0111] In some embodiments, the phosphorylated tau accumulation occurs in the CA1 and uncus of the subject's brain.

[0112] In some embodiments, the subject exhibits no or minimal systemic toxicity comparable to a control subject before or without administration.

[0113] In some embodiments, the subject exhibits no or minimal hepatotoxicity comparable to a control subject before or without administration.

[0114] In some embodiments, hepatotoxicity is evaluated by the alkaline phosphatase (ALP) level, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, total bilirubin (T-bil) level, ammonia (NH3) level, or any combination thereof in the subject.

[0115] In some embodiments, the subject exhibits no or minimal nephrotoxicity comparable to a control subject before or without administration.

[0116] In some embodiments, nephrotoxicity is evaluated by the lactate (Lac) level, blood urea nitrogen (BUN) level, creatinine (Crea) level, or any combination thereof in the subject.

[0117] In some embodiments, the subject exhibits no or minimal altered lipid metabolism comparable to a control subject before or without administration.

[0118] In some embodiments, lipid metabolism is evaluated by the lipase (Lip) level, high density lipoprotein (HDL) level, low density lipoprotein (LDL) level, total cholesterol (T-Chol) level, triglyceride (TG) level, or any combination thereof in the subject.

[0119] In some embodiments, the subject exhibits no or minimal altered calcium homeostasis comparable to a control subject before or without administration.

[0120] In some embodiments, calcium homeostasis is evaluated by the calcium (Ca) level, phosphorus (P) level, or a combination thereof in a subject.

[0121] In some embodiments, the blood-brain barrier permeation of a compound in the subject's brain is increased compared to the blood-brain barrier permeation of a compound having the same structure to which a ligand molecule for GLUT or a functional analog thereof is not linked.

[0122] In some embodiments, the retention time and / or distribution of a compound in the subject's brain is increased compared to the retention time and / or distribution of a compound having the same structure to which a ligand molecule for GLUT or a functional analog thereof is not linked.

[0123] In some embodiments, a compound is specifically delivered by one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT.

[0124] In some embodiments, the expression and / or activity of a target molecule is reduced or inhibited to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT.

[0125] In some embodiments, one or more tissues, organs, or cells that express GLUT include the brain, blood, brain, intestine, liver, kidney, pancreas, embryo, testis, placenta, muscle, heart, fat, adipose tissue, spleen, colon, prostate, testis, blastocyst, skeletal muscle, white adipose tissue, brown adipose tissue, or any combination thereof.

[0126] In some embodiments, (i) GLUT is GLUT1, and one or more tissues, organs, or cells that express GLUT include the brain, blood, or a combination thereof; (ii) The GLUT is GLUT2, and one or more tissues, organs, or cells that express GLUT include the brain, intestine, liver, kidney, pancreas, or any combination thereof; (iii) The GLUT is GLUT3, and one or more tissues, organs, or cells that express GLUT include the brain, embryo, testis, placenta, or any combination thereof; (iv) The GLUT is GLUT4, and one or more tissues, organs, or cells that express GLUT include the brain, muscle, heart, fat, adipose tissue, or any combination thereof; (v) The GLUT is GLUT5, and one or more tissues, organs, or cells that express GLUT include the brain, intestine, testis, muscle, kidney, fat, or any combination thereof; (vi) The GLUT is GLUT6, and one or more tissues, organs, or cells that express GLUT include the brain, spleen, or a combination thereof; (vii) The GLUT is GLUT7, and one or more tissues, organs, or cells that express GLUT include the intestine, colon, prostate, testis, prostate, or any combination thereof; (viii) The GLUT is GLUT8, and one or more tissues, organs, or cells that express GLUT include the brain, testis, liver, spleen, fat, blastocyst, or any combination thereof; (ix) The GLUT is GLUT9, and one or more tissues, organs, or cells that express GLUT include the liver, kidney, intestine, colon, or any combination thereof; (x) The GLUT is GLUT10, and one or more tissues, organs, or cells that express GLUT include the liver, pancreas, fat, skeletal muscle, heart, adipose tissue, placenta, kidney, or any combination thereof; (xi) The GLUT is GLUT11, and one or more tissues, organs, or cells that express GLUT include the heart, muscle, kidney, pancreas, placenta, or any combination thereof; (xii) The GLUT is GLUT12, and one or more tissues, organs, or cells that express GLUT include the brain, muscle, heart, fat, pancreas, prostate, adipose tissue, placenta, kidney, or any combination thereof; (xiii) The GLUT is GLUT13, and one or more tissues, organs, or cells that express GLUT include the brain, white adipose tissue, brown adipose tissue, kidney, or any combination thereof; or (xiv) The GLUT is GLUT14, and one or more tissues, organs, or cells that express GLUT include the testis.

[0127] In some embodiments, (i) the GLUT is GLUT1, and one or more tissues, organs, or cells that express GLUT include the blood-brain barrier, astrocytes, erythrocytes, or any combination thereof; (ii) the GLUT is GLUT2, and one or more tissues, organs, or cells that express GLUT include astrocytes, gastrointestinal tract, small intestine, intestinal absorptive epithelial cells, hepatocytes, pancreatic β cells, brain nuclei, nucleus of the solitary tract, motor nucleus of the vagus nerve, paraventricular nucleus of the hypothalamus, lateral hypothalamic area, arcuate nucleus, and olfactory bulb, or any combination thereof; (iii) the GLUT is GLUT3, and one or more tissues, organs, or cells that express GLUT include neurons, blood-brain barrier, astrocytes, sperm, spermatozoa, fibroblasts, platelets, retinal endothelial cells, leukocytes, or any combination thereof; (iv) the GLUT is GLUT4, and one or more tissues, organs, or cells that express GLUT include neurons, adipocytes, skeletal muscle cells, cardiomyocytes, hypothalamus, cerebellum, cortex, and hippocampus, or a combination thereof; (v) the GLUT is GLUT5, and one or more tissues, organs, or cells that express GLUT include microglia, blood-brain barrier, small intestine, apical membrane of intestinal cells, plasma membrane of mature sperm, skeletal muscle, or any combination thereof; (vi) The GLUT is GLUT6, and one or more tissues, organs, or cells expressing GLUT include leukocytes, peripheral leukocytes, testicular germ cells, or any combination thereof; (vii) The GLUT is GLUT7, and one or more tissues, organs, or cells expressing GLUT include the small intestine; (viii) The GLUT is GLUT8, and one or more tissues, organs, or cells expressing GLUT include neurons, brown adipose tissue, cerebellum, adrenal gland, spermatocytes, mature sperm, or any combination thereof; (ix) The GLUT is GLUT9, and one or more tissues, organs, or cells expressing GLUT include the small intestine, leukocytes, chondrocytes, or any combination thereof; (x) The GLUT is GLUT10, and one or more tissues, organs, or cells expressing GLUT include white fat; (xi) The GLUT is GLUT12, and one or more tissues, organs, or cells expressing GLUT include astrocytes, prostate, small intestine, chondrocytes, or any combination thereof; or (xii) The GLUT is GLUT13, and one or more tissues, organs, or cells expressing GLUT include neurons.

[0128] In some embodiments, one or more tissues, organs, or cells expressing GLUT include cancer cells.

[0129] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, gastric cancer, colorectal cancer, and any combination thereof.

[0130] In some embodiments, (i) the GLUT is GLUT1, and the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, and any combination thereof; (ii) The GLUT is GLUT3, and the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, cervical cancer, kidney cancer, lung cancer, glioblastoma, and any combination thereof; (iii) The GLUT is GLUT5, and the cancer is selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, leukemia, and any combination thereof; (iv) The GLUT is GLUT10, and the cancer is leukemia; (v) The GLUT is GLUT12, and the cancer is breast cancer; or (vi) The GLUT is GLUT14, and the cancer is brain cancer.

[0131] In some embodiments, (i) the target molecule is BACE1-AS, and the administration results in improvement of memory and learning behaviors; (ii) the target molecule is BACE1, and the administration results in a decrease in amyloid plaque rate, improvement of neuropathological and behavioral symptoms, suppression of BACE1 expression and / or activity, reduction of plaque burden in the cerebral cortex and hippocampus, increase in the level of synaptophysin, relief of memory loss, or any combination thereof; (iii) the target molecule is presenilin 1 (PS1), and the administration results in a reduction in the level of Aβ42; (iv) the target molecule is ROCK-II, and the administration results in promotion of axonal regeneration; (v) the target molecule is I2 PP-2A, and the administration results in a decrease in the levels of Aβ, APP, and phosphorylated tau, improvement of memory and learning ability, or a combination thereof; (vi) the target molecule is ACAT-1, and the administration results in reduction of the enzymatic process of APP, enhancement of the level of free cholesterol, or a combination thereof; (vii) the target molecule is Nogo receptor, and the administration results in promotion of the regeneration and repair of cholinergic neurons; (viii) the target molecule is mutant presenilin 1 (L392V PS-1), BACE1, or a combination thereof, and the administration results in a decrease in amyloid plaque levels; (ix) The target molecule is APP, Tau, VDAC1, or a combination thereof, and administration results in improved synaptic activity and mitochondrial function; (x) The target molecule is α-synuclein (SNCA), and administration results in a reduction in SNCA levels, a reduction in hSNCA-mediated behavioral deficits, improvement in motor dysfunction, cell protection from apoptosis-induced cell death, a reduction in α-syn accumulation, improvement in inflammatory pathologies, or any combination thereof; (xi) The target molecule is Htt, and administration results in inhibition of Htt expression and / or activity, a decrease in the size and number of neuronal nuclear inclusions (NII), improvement in motor deficits, neuronal survival, a decrease in the level of mutant htt protein, or any combination thereof; (xii) The target molecule is T-bet, and administration results in regulation of interferon (IFN), prevention of disease onset, or a combination thereof; (xiii) The target molecule is Notch1, and administration results in improved motor function, repair in histopathological sections, or a combination thereof; (xiv) The target molecule is LINGO-1, and administration results in improvement in memory and learning behaviors; (xv) The target molecule is NR4A2, and administration results in inhibition of the pathogenic potential of IFN and IL-17; (xvi) The target molecule is TRIF, and administration results in alleviation of disease severity through inhibition of interleukin and cytokine release; (xvii) The target molecule is caspase-2, and administration results in inhibition of neuronal loss, a decrease in the thickness of the retinal nerve fiber layer (RNFL), an increase in the survival of retinal ganglion cells (RGCs), or any combination thereof; (xviii) The target molecule is CaMKII, and administration results in reduction of mechanical and thermal hypersensitivity, reduction of induced and non-induced pain, or a combination thereof; (xix) The target molecule is GFAP, vimentin, or a combination thereof, and administration results in improvement in urinary function; (xx) The target molecule is EphB3, and administration results in improved axonal regeneration, improved motor function, or a combination thereof; (xxi) The target molecule is iNOS, and administration results in improvement of secondary injury after spinal cord injury; (xxii) The target molecule is Nischarin, and administration results in improvement of motor function; or (xxiii) The target molecule is RhoA, and administration results in improvement of walking, reduction of allodynia, or a combination thereof.

[0132] In another aspect, Formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A method for targeted delivery of a compound comprising the structure of Formula 20 to a specific tissue, organ or cell in a subject in need of targeted delivery of the compound comprising the structure of Formula 20, (i) Covalently linking a ligand molecule or a functional analog thereof for a glucose transporter (GLUT) via a second linker or bond to the A terminus, B terminus or a combination thereof of a compound comprising the structure of Formula 20, (ii) Administering to the subject comprising, wherein the specific tissue, organ or cell expresses GLUT, and the compound is delivered to the specific tissue, organ or cell to a greater extent by the specific tissue, organ or cell compared to a tissue, organ or cell that does not express GLUT, a method is provided herein.

[0133] In another aspect, a compound for targeted delivery to a specific tissue, organ, or cell in a subject in need of targeted delivery to the specific tissue, organ or cell, the compound having the formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker)) comprises the structure of, a ligand molecule for a glucose transporter (GLUT) or a functional analogue thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B or a combination thereof, a specific tissue, organ or cell expresses GLUT, when administered to a subject, the compound is delivered to a specific tissue, organ or cell to a greater extent than to tissues, organs or cells that do not express GLUT, compounds are provided herein.

[0134] In some embodiments, R is an inhibitory oligonucleotide molecule.

[0135] In another aspect, a method of reducing or inhibiting the expression and / or activity of a target molecule in a specific tissue, organ or cell in a subject in need of such reduction or inhibition of the expression and / or activity of the target molecule in the specific tissue, organ or cell, the method comprising administering to the subject a therapeutically effective amount of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker)) comprising administering a compound comprising the structure of, a ligand molecule for a glucose transporter (GLUT) or a functional analogue thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B or a combination thereof, A specific tissue, organ or cell expresses GLUT, The present specification provides a method in which a compound reduces or inhibits the expression and / or activity of a target molecule in a specific tissue, organ or cell to a greater extent compared to the expression and / or activity of the target molecule in a tissue, organ or cell that does not express GLUT.

[0136] In another aspect, a compound for reducing or inhibiting the expression and / or activity of a target molecule in a specific tissue, organ or cell in a subject in need thereof, the compound having the formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) comprises the structure of, a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, a specific tissue, organ or cell expresses GLUT, The present specification provides a compound in which the compound reduces or inhibits the expression and / or activity of a target molecule in a specific tissue, organ or cell to a greater extent compared to the expression and / or activity of the target molecule in a tissue, organ or cell that does not express GLUT.

[0137] In some embodiments, the linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical Formula

Chemical formula

[0138] In some embodiments, the compound is of Formula 18 or Formula 19: (L i )-A-X-R-Y-B Formula 18, or A-X-R-Y-B-(L j ) Formula 19 (wherein L is a ligand molecule for GLUT or a functional analog thereof, i and j are independently integers from 0 to 10, when i is 0, j is an integer from 1 to 10, and when j is 0, i is an integer from 1 to 10) and includes the structure of.

[0139] In some embodiments, the ligand molecule for GLUT is a sugar.

[0140] In some embodiments, the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose.

[0141] In some embodiments, the ligand molecule for GLUT is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, trehalose, and urate.

[0142] In some embodiments, GLUT is selected from the group consisting of GLUT1 to GLUT14.

[0143] In some embodiments, the ligand molecule for GLUT is fructose, and GLUT is selected from the group consisting of GLUT2, GLUT5, GLUT7, GLUT8, GLUT9, GLUT11, and GLUT12.

[0144] In some embodiments, the ligand molecule for GLUT is galactose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, and GLUT14.

[0145] In some embodiments, the ligand molecule for GLUT is glucose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, and GLUT12.

[0146] In some embodiments, the ligand molecule for GLUT is mannose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4.

[0147] In some embodiments, the ligand molecule for GLUT is xylose, and GLUT is GLUT3.

[0148] In some embodiments, the ligand molecule for GLUT is dehydroascorbic acid, and GLUT is GLUT4.

[0149] In some embodiments, the ligand molecule for GLUT is trehalose, and GLUT is GLUT8.

[0150] In some embodiments, the ligand molecule for GLUT is uric acid, and GLUT is GLUT9.

[0151] In some embodiments, R is a double-stranded oligonucleotide molecule or a single-stranded oligonucleotide molecule.

[0152] In some embodiments, R reduces or inhibits the expression and / or activity of the target molecule.

[0153] In some embodiments, the target molecule is any one selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA.

[0154] In some embodiments, the inhibitory oligonucleotide molecule is siRNA, shRNA, miRNA, amiRNA, an antisense oligonucleotide molecule, an RNAi agent, or any combination thereof.

[0155] In some embodiments, R is a double-stranded oligonucleotide molecule comprising a sense strand and an antisense strand containing a sequence complementary to the sense strand.

[0156] In some embodiments, the sense strand or the antisense strand is 19 to 31 nucleotides in length.

[0157] In some embodiments, at least one phosphate group is linked to the 5' end of the antisense strand.

[0158] In some embodiments, the compound has the formula 2: A-X-S-Y-B AS Formula 2 (wherein S is the sense strand and AS is the antisense strand) and comprises the structure of.

[0159] In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 50 oligonucleotides, 10 to 40 oligonucleotides, or 15 to 30 oligonucleotides.

[0160] In some embodiments, R is DNA, RNA, or a combination thereof.

[0161] In some embodiments, R includes backbone modifications including phosphorothioate linkages, phosphorodiamidate linkages, boranophosphate linkages, methylphosphonate linkages, or any combination thereof.

[0162] In some embodiments, R includes locked nucleic acids, peptide nucleic acids, unlocked nucleic acids, or any combination thereof.

[0163] In some embodiments, R includes a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, a 2'-methyl moiety, a 2'-methoxyl moiety, a 2'-amine moiety, a 2'-O-propyl moiety, a 2'-O-2-methylthioethyl moiety, a 2'-O-3-aminopropyl moiety, a 2'-O-3-dimethylaminopropyl moiety, a 2'-O-N-methylacetamino moiety or a 2'-O-dimethylamidooxyethyl moiety.

[0164] In some embodiments, R includes a modified sugar moiety.

[0165] In some embodiments, the hydrophilic moiety is any one selected from the group consisting of polyethylene glycol (PEG), polyvinylpyrrolidone, and polyoxazoline.

[0166] In some embodiments, the compound is of formula 7 or formula 8: (A’ m -J) n -X-R-Y-B Formula 7, (J-A’ m ) n -X-R-Y-B Formula 8 (wherein A’ is a monomer hydrophilic moiety, J is PO3 - , SO3 - and CO2 - selected from the group consisting of, connects A’ to each other, or connects A’ to X, m is an integer from 1 to 15, n is an integer from 1 to 10, A’ is Compound 1, Compound 2, and Compound 3

Chemical Structure

Chemical Structure

Chemical Structure

[0167] In some embodiments, the molecular weight of the hydrophilic moiety is from 200 to 10,000.

[0168] In some embodiments, the hydrophobic moiety is a steroid derivative, glyceride derivative, glycerol ether, polypropylene glycol, unsaturated or saturated C 12 ~C 50 , and is any one selected from the group consisting of diacyl phosphatidylcholine, fatty acid, phospholipid, lipopolyamine, lipid, tocopherol, and tocotrienol.

[0169] In some embodiments, the steroid derivative is any one selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cotestanyl formate, and cholestanyl amine.

[0170] In some embodiments, the glyceride derivative is any one selected from the group consisting of monoglycerides, diglycerides, and triglycerides.

[0171] In some embodiments, the molecular weight of the hydrophobic moiety is from 250 to 1,000.

[0172] In some embodiments, X and Y are independently non-cleavable bonds or cleavable bonds.

[0173] In some embodiments, the non-cleavable bond is an amide bond or a phosphorylated bond.

[0174] In some embodiments, the cleavable bond is any one selected from the group consisting of a disulfide bond, an acid-cleavable bond, an ester bond, an anhydride bond, a biodegradable bond, and an enzyme-cleavable bond.

[0175] In some embodiments, the compound is formulated as nanoparticles.

[0176] In some embodiments, the compound is formulated as a composition.

[0177] In some embodiments, the composition is formulated as a pharmaceutical composition, and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0178] In some embodiments, specific tissues, organs, or cells expressing GLUT include the brain, blood, brain, intestine, liver, kidney, pancreas, embryo, testis, placenta, muscle, heart, fat, adipose tissue, spleen, colon, prostate, testis, blastocyst, skeletal muscle, white adipose tissue, brown adipose tissue, or any combination thereof.

[0179] In some embodiments, (i) GLUT is GLUT1, and specific tissues, organs, or cells expressing GLUT include the brain, blood, or a combination thereof; (ii) The GLUT is GLUT2, and the specific tissues, organs, or cells expressing GLUT include the brain, intestine, liver, kidney, pancreas, or any combination thereof; (iii) The GLUT is GLUT3, and the specific tissues, organs, or cells expressing GLUT include the brain, embryo, testis, placenta, or any combination thereof; (iv) The GLUT is GLUT4, and the specific tissues, organs, or cells expressing GLUT include the brain, muscle, heart, fat, adipose tissue, or any combination thereof; (v) The GLUT is GLUT5, and the specific tissues, organs, or cells expressing GLUT include the brain, intestine, testis, muscle, kidney, fat, or any combination thereof; (vi) The GLUT is GLUT6, and the specific tissues, organs, or cells expressing GLUT include the brain, spleen, or a combination thereof; (vii) The GLUT is GLUT7, and the specific tissues, organs, or cells expressing GLUT include the intestine, colon, prostate, testis, prostate, or any combination thereof; (viii) The GLUT is GLUT8, and the specific tissues, organs, or cells expressing GLUT include the brain, testis, liver, spleen, fat, blastocyst, or any combination thereof; (ix) The GLUT is GLUT9, and the specific tissues, organs, or cells expressing GLUT include the liver, kidney, intestine, colon, or any combination thereof; (x) The GLUT is GLUT10, and the specific tissues, organs, or cells expressing GLUT include the liver, pancreas, fat, skeletal muscle, heart, adipose tissue, placenta, kidney, or any combination thereof; (xi) The GLUT is GLUT11, and the specific tissues, organs, or cells expressing GLUT include the heart, muscle, kidney, pancreas, placenta, or any combination thereof; (xii) The GLUT is GLUT12, and the specific tissues, organs, or cells expressing GLUT include the brain, muscle, heart, fat, pancreas, prostate, adipose tissue, placenta, kidney, or any combination thereof; (xiii) The GLUT is GLUT13, and the specific tissues, organs, or cells expressing GLUT include the brain, white adipose tissue, brown adipose tissue, kidney, or any combination thereof; or (xiv) The GLUT is GLUT14, and the specific tissues, organs, or cells expressing GLUT include the testis.

[0180] In some embodiments, (i) the GLUT is GLUT1, and the specific tissues, organs, or cells expressing GLUT include the blood-brain barrier, astrocytes, erythrocytes, or any combination thereof; (ii) the GLUT is GLUT2, and the specific tissues, organs, or cells expressing GLUT include astrocytes, gastrointestinal tract, small intestine, intestinal absorptive epithelial cells, hepatocytes, pancreatic β cells, brain nuclei, solitary tract nucleus, vagus nerve motor nucleus, paraventricular nucleus of the hypothalamus, lateral hypothalamic area, arcuate nucleus, and olfactory bulb, or any combination thereof; (iii) the GLUT is GLUT3, and the specific tissues, organs, or cells expressing GLUT include neurons, blood-brain barrier, astrocytes, sperm, spermatozoa, fibroblasts, platelets, retinal endothelial cells, leukocytes, or any combination thereof; (iv) the GLUT is GLUT4, and the specific tissues, organs, or cells expressing GLUT include neurons, adipocytes, skeletal muscle cells, cardiomyocytes, hypothalamus, cerebellum, cortex, and hippocampus, or a combination thereof; (v) the GLUT is GLUT5, and the specific tissues, organs, or cells expressing GLUT include microglia, blood-brain barrier, small intestine, apical membrane of intestinal cells, plasma membrane of mature sperm, skeletal muscle, or any combination thereof; (vi) The GLUT is GLUT6, and the specific tissue, organ, or cell that expresses GLUT includes leukocytes, peripheral leukocytes, testicular germ cells, or any combination thereof; (vii) The GLUT is GLUT7, and the specific tissue, organ, or cell that expresses GLUT includes the small intestine; (viii) The GLUT is GLUT8, and the specific tissue, organ, or cell that expresses GLUT includes neurons, brown adipose tissue, the cerebellum, the adrenal gland, spermatocytes, mature sperm, or any combination thereof; (ix) The GLUT is GLUT9, and the specific tissue, organ, or cell that expresses GLUT includes the small intestine, leukocytes, chondrocytes, or any combination thereof; (x) The GLUT is GLUT10, and the specific tissue, organ, or cell that expresses GLUT includes white fat; (xi) The GLUT is GLUT12, and the specific tissue, organ, or cell that expresses GLUT includes astrocytes, the prostate, the small intestine, chondrocytes, or any combination thereof; or (xii) The GLUT is GLUT13, and the specific tissue, organ, or cell that expresses GLUT includes neurons.

[0181] In some embodiments, the specific tissue, organ, or cell that expresses GLUT includes cancer cells.

[0182] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, gastric cancer, colorectal cancer, and any combination thereof.

[0183] In some embodiments, (i) the GLUT is GLUT1, and the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, and any combination thereof; (ii) The GLUT is GLUT3, and the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, cervical cancer, kidney cancer, lung cancer, glioblastoma, and any combination thereof; (iii) The GLUT is GLUT5, and the cancer is selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, leukemia, and any combination thereof; (iv) The GLUT is GLUT10, and the cancer is leukemia; (v) The GLUT is GLUT12, and the cancer is breast cancer; or (vi) The GLUT is GLUT14, and the cancer is brain cancer.

[0184] In another aspect, formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A method for increasing the blood-brain barrier permeability of a compound comprising the structure of formula 20 in a subject in need of increasing the blood-brain barrier permeability of a compound comprising the structure of formula 20, (i) Covalently linking a ligand molecule or a functional analog thereof to a GLUT via a second linker or bond to the A terminus, B terminus, or a combination thereof of a compound comprising the structure of formula 20, (ii) Administering to the subject comprising, The present specification provides a method wherein the compound exhibits greater blood-brain barrier permeability in the subject as compared to a compound having the same structure to which a ligand molecule or a functional analog thereof to a GLUT is not linked.

[0185] In another aspect, formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A compound comprising the structure of, with increased blood-brain barrier permeability, A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, When administered to a subject, the compound exhibits blood-brain barrier permeability in the subject to a greater extent compared to a compound having the same structure to which a ligand molecule for GLUT or a functional analog thereof is not linked. A compound is provided herein.

[0186] In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical formula

Chemical formula

[0187] In some embodiments, the compound is of Formula 18 or Formula 19: (L i )-A-X-R-Y-B Formula 18, or A-X-R-Y-B-(L j ) Formula 19 (wherein L is a ligand molecule for GLUT or a functional analog thereof, i and j are independently integers from 0 to 10, When i is 0, j is an integer from 1 to 10, and when j is 0, i is an integer from 1 to 10) includes the structure of

[0188] In some embodiments, the ligand molecule for GLUT is a sugar.

[0189] In some embodiments, the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose.

[0190] In some embodiments, GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12, and GLUT13.

[0191] In some embodiments, the ligand molecule for GLUT is fructose, and GLUT is selected from the group consisting of GLUT2, GLUT5, GLUT8, and GLUT12.

[0192] In some embodiments, the ligand molecule for GLUT is galactose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4.

[0193] In some embodiments, the ligand molecule for GLUT is glucose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT6, GLUT8, and GLUT12.

[0194] In some embodiments, the ligand molecule for GLUT is mannose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4.

[0195] In some embodiments, the ligand molecule for GLUT is xylose, and GLUT is GLUT3.

[0196] In some embodiments, the ligand molecule for GLUT is dehydroascorbic acid and the GLUT is GLUT4.

[0197] In some embodiments, the ligand molecule for GLUT is trehalose and the GLUT is GLUT8.

[0198] In some embodiments, R is a double-stranded oligonucleotide molecule or a single-stranded oligonucleotide molecule.

[0199] In some embodiments, R reduces or inhibits the expression and / or activity of the target molecule.

[0200] In some embodiments, the target molecule is any one selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA.

[0201] In some embodiments, the inhibitory oligonucleotide molecule is siRNA, shRNA, miRNA, amiRNA, an antisense oligonucleotide molecule, an RNAi agent, or any combination thereof.

[0202] In some embodiments, R is a double-stranded oligonucleotide molecule comprising a sense strand and an antisense strand containing a sequence complementary to the sense strand.

[0203] In some embodiments, the sense strand or the antisense strand is 19 to 31 nucleotides in length.

[0204] In some embodiments, at least one phosphate group is linked to the 5' end of the antisense strand.

[0205] In some embodiments, the compound has the formula 2: A-X-S-Y-B AS Formula 2 (where S is the sense strand and AS is the antisense strand) and includes the structure of.

[0206] In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 50 oligonucleotides, 10 to 40 oligonucleotides, or 15 to 30 oligonucleotides.

[0207] In some embodiments, R is DNA, RNA, or a combination thereof.

[0208] In some embodiments, R includes backbone modifications including phosphorothioate linkages, phosphorodiamidate linkages, boranophosphate linkages, methylphosphonate linkages, or any combination thereof.

[0209] In some embodiments, R includes locked nucleic acids, peptide nucleic acids, unlocked nucleic acids, or any combination thereof.

[0210] In some embodiments, R includes a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, a 2'-methyl moiety, a 2'-methoxyl moiety, a 2'-amine moiety, a 2'-O-propyl moiety, a 2'-O-2-methylthioethyl moiety, a 2'-O-3-aminopropyl moiety, a 2'-O-3-dimethylaminopropyl moiety, a 2'-O-N-methylacetamino moiety, or a 2'-O-dimethylamidooxyethyl moiety.

[0211] In some embodiments, R includes a modified sugar moiety.

[0212] In some embodiments, the hydrophilic moiety is any one selected from the group consisting of polyethylene glycol (PEG), HEG (hexaethylene glycol), polyvinylpyrrolidone, and polyoxazoline.

[0213] In some embodiments, the compound has the formula 7 or formula 8: (A’ m -J) n -X-R-Y-B Formula 7, (J-A’ m ) n -X-R-Y-B Formula 8 (wherein, A’ is a monomeric hydrophilic moiety, J is selected from the group consisting of PO3 - , SO3 - and CO2 - and either links A’ to each other or links A’ to X, m is an integer from 1 to 15, n is an integer from 1 to 10, A’ is any one selected from the group consisting of Compound 1, Compound 2, and Compound 3

Chemical formula

Chemical formula

Chemical formula

[0214] In some embodiments, the molecular weight of the hydrophilic moiety is from 200 to 10,000.

[0215] In some embodiments, the hydrophobic moiety is any one selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycol, unsaturated or saturated C 12 ~C 50 , diacyl phosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols, and tocotrienols.

[0216] In some embodiments, the steroid derivative is any one selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cotestanyl formate, and cholestanyl amine.

[0217] In some embodiments, the glyceride derivative is any one selected from the group consisting of monoglycerides, diglycerides, and triglycerides.

[0218] In some embodiments, the molecular weight of the hydrophobic moiety is from 250 to 1,000.

[0219] In some embodiments, X and Y are independently non-cleavable bonds or cleavable bonds.

[0220] In some embodiments, the non-cleavable bond is an amide bond or a phosphorylation bond.

[0221] In some embodiments, the cleavable bond is any one selected from the group consisting of disulfide bonds, acid-cleavable bonds, ester bonds, anhydride bonds, biodegradable bonds, and enzyme-cleavable bonds.

[0222] In some embodiments, the blood-brain barrier permeation of the compound is mediated through GLUT-mediated ligand uptake into cells and GLUT-mediated ligand efflux across the blood-brain barrier.

[0223] In some embodiments, the compound is formulated as nanoparticles.

[0224] In some embodiments, the compound is formulated as a composition.

[0225] In some embodiments, the composition is formulated as a pharmaceutical composition, which further comprises a pharmaceutically acceptable excipient, carrier, or diluent.

Brief Description of the Drawings

[0226] Figure 1 is a diagram showing the pathway through GLUT. In some embodiments, receptor targeting chemistry is combined with SAMiRNA™ technology to enable the delivery of siRNA and effective KD to the central nervous system (CNS).

[0227] Figure 2 is a scheme showing that an exemplary embodiment of a BBB targeting ligand on a hydrophilic terminus enhances intravenous siRNA delivery by more than 20-fold. The CNS-SAMiRNA™ platform incorporates a BBB targeting ligand into an existing SAMiRNA™ platform, which doubly conjugates the terminus of the RNA sense strand with a hydrophilic moiety and a hydrophobic moiety to enable self-assembly into nanoparticles.

[0228] Figure 3 shows the DMTr protection, tetra-acetylation, DMTr deprotection, and 6-alcohol protection (trifluoromethanesulfonate) process of D-(+)-glucose in Example 1.

[0229] Figure 4 shows Example 2 of the amine TFA protection (6-aminohexanoic acid) process.

[0230] Figure 5 shows the amine TFA protection (3-amino-1,2-propanediol), DMT protection (3-amino-1,2-propanediol), and TFA deprotection (3-amino-1,2-propanediol) processes of Example 3.

[0231] Figure 6 shows the amide coupling (6-aminohexanoic acid + 3-amino-1,2-propanediol) and amine-TFA deprotection (6-aminohexanoic acid + 3-amino-1,2-propanediol) processes of Example 4.

[0232] Figure 7 shows the amine addition, amine-TFA protection, succinylation, CPG coupling, and capping processes of Example 5.

[0233] Figure 8 shows the structure of the sense strand conjugated with glucose synthesized according to Example 6.

[0234] Figure 9 shows the micelle qNANO size distribution of Example 7.

[0235] Figure 10 shows the results of immunocytochemistry (ICC) regarding the entry of particles into Neuro-2A cells after treating the particles with various glucose-SAMiRNA(trademark)-cy5 / SAMiRNA(trademark)-cy5 ratios under culture medium conditions with different glucose contents.

[0236] Figures 11A - 11D show longer residence times in the brain, which implies improved bioavailability and potentially a more favorable dosing schedule. Figure 11A is a scheme showing an exemplary research design. Figure 11B shows ex vivo fluorescence brain images after intravenous (IV) administration of Cy5-labeled CNS-SAMiRNA™ obtained by IVIS-200, Perkin Elmer. After intravenous administration of glucose-SAMiRNA™-cy5 of Example 9-2 into the lateral tail vein of mice, results of IVIS200 measurements of cy5 fluorescence were obtained from brain tissues excised on different days. Figure 11C shows the average radiation efficiency of the ex vivo images. For example, the graph analyzes the average radiation efficiency per day as compared to seconds to minutes for typical RNAi. Figure 11D shows a quantitative analysis of CNS-brain (''ligand-SAMiRNA™'') in whole brain tissue compared to non-targeted SAMiRNA™ (''SAMiRNA™''). The graph shows the delivery rate with respect to the amount of glucose-SAMiRNA™-cy5 administered per gram of brain tissue of Example 9-3.

[0237] Figure 12A shows a photograph of the results of confocal imaging of cy5 fluorescence on the sagittal section side of brain tissues extracted on different days after intravenous administration of glucose-SAMiRNA™-cy5 in Example 9-4 into the lateral tail vein of mice. Bar = 1000 μm. Figure 12B shows an enlarged confocal image of cy5 fluorescence on the sagittal section side of brain tissues extracted 2 days after intravenous administration of glucose-SAMiRNA™-cy5 in Example 9-4 into the lateral tail vein of mice. Bar = 1000 μm (upper panel). 40 μm (lower panel), 10 μm (box in the lower panel); obtained by DragonFly, Andor. Figure 12C shows a photograph of the results for each part of the cy5 fluorescence on the sagittal section side of brain tissues extracted 2 days after intravenous administration of glucose-SAMiRNA™-cy5 in Example 9-4 as shown in the upper panel of Figure 12B. Names of each part: 1; olfactory bulb, 2; septum, 3; ventricle 3v, 4; hippocampus, 5; cerebral cortex white matter, 6; cerebral cortex gray-white matter, 7; thalamus, 8; hypothalamus, 9; midbrain, 10; ventricle 4v, 11; ventricle 4v, 12; choroid plexus 4v, 13; cerebellar nuclei, 14; cerebellar cortex, 15; pons, 16; medulla oblongata.

[0238] Figure 13 shows the potential for a wide range of CNS indications enabled by the effective delivery and distribution of the exemplary compounds provided herein into the brain. The IV delivery of the exemplary compounds provided herein across the BBB distributes throughout all parts of the brain, particularly to the deepest parts, as compared to the intrathecal delivery of a comparator compound via cerebrospinal fluid (CSF) that distributes predominantly to the outer parts of the brain (lower panel). Names of each part: 1; olfactory bulb, 2; septum, 3; ventricle 3v, 4; hippocampus, 5; cerebral cortex white matter, 6; cerebral cortex gray-white matter, 7; thalamus, 8; hypothalamus, 9; midbrain, 10; ventricle 4v, 11; ventricle 4v, 12; choroid plexus 4v, 13; cerebellar nuclei, 14; cerebellar cortex, 15; pons, 16; medulla oblongata.

[0239] Figure 14 shows the potential for a wide range of CNS indications enabled by the effective delivery and distribution of the exemplary compounds provided herein into the brain. The left panel shows an image of the distribution along with the names of each part: 1; olfactory bulb, 2; septum, 3; ventricle 3v, 4; hippocampus, 5; cerebral cortex white matter, 6; cerebral cortex gray-white matter, 7; thalamus, 8; hypothalamus, 9; midbrain, 10; ventricle 4v, 11; ventricle 4v, 12; choroid plexus 4v, 13; cerebellar nuclei, 14; cerebellar cortex, 15; pons, 16; medulla oblongata. The right panel shows a plot of the fluorescence intensity for each of the 16 tissues on day 2.

[0240] Figures 15A-15B show immunofluorescence confocal images of astrocytes, BCECs, and Cy5-labeled CNS-SAMiRNA™ (Figure 15A; hippocampal region, Figure 15B; hypothalamic region to verify BBB penetration). White arrows, SAMiRNA™; white dotted lines, BBB. Figure 15A shows that an exemplary embodiment of the CNS platform provided herein crosses the BBB for delivery to the hippocampus, a deep region of the temporal lobe for learning and memory. Figure 15B shows good delivery of an exemplary embodiment of the CNS platform provided herein to the hypothalamus of the forebrain, which is responsible for autonomic function, sleep, and emotions. Figures 15C-15D show immunofluorescence confocal images of neurons (Figure 15C; cortex, Figure 15D; hypothalamus) of brain tissue extracted after intravenous administration of glucose-SAMiRNA™-cy5 in Examples 9-5, demonstrating neuronal delivery of an exemplary embodiment of the CNS platform provided herein, confirmed in the hypothalamus and cerebral cortex responsible for consciousness. Figure 15C shows an immunofluorescence image of neurons and Cy5-labeled CNS-SAMiRNA™ in the cerebral cortex region. Figure 15D shows the hypothalamic region for verifying co-localization of CNS-SAMiRNA™ neurons. Scale bar, 200 or 50 μm; section, 50 μm; acquisition, Dragonfly, Andor; white dotted lines, neurons. Figure 15A. Hippocampus, astrocytes; green, BCEC; yellow, nucleus; blue, red; glu-SAMiRNA™. Figure 15B. Hypothalamus, astrocytes; green, BCEC; yellow, nucleus; blue, red; glu-SAMiRNA™. Figure 15C. Cortex, neurons; green, blue; nucleus, red; glu-SAMiRNA™. Figure 15D. Hypothalamus, neurons; green, blue; nucleus, red; glu-SAMiRNA™. Figure 15E. 3V choroid plexus, astrocytes; green, BCEC; yellow, nucleus; blue, red; glu-SAMiRNA™. Figure 15F. 3V, astrocytes; green, BCEC; yellow, nucleus; blue, red; glu-SAMiRNA™.

[0241] Figure 16 shows a graph representing the results of stem-loop qPCR relative quantification of residual glucose-SAMiRNA (trademark) in each part of the brain tissue extracted on different days after intravenous administration of glucose-SAMiRNA (trademark) in Examples 9-6. The initial PK, like the data shown, suggests two delivery pathways via the BBB and CSF.

[0242] Figure 17 shows that a proof-of-concept (PoC) study for an exemplary embodiment of the CNS platform provided herein targeting a neuronal marker or a housekeeping gene confirms knockdown (KD) in important brain disease regions by IV or subcutaneous (SC) administration in normal mice. Exemplary embodiments of the CNS platform provided herein show impressive inhibition of Map2, a neuronal marker, or Gapdh, a housekeeping gene, in important brain regions by both IV and SC administration. n, 3; P value, t-test. The left panel shows an image of the distribution along with the name of each part: 1; olfactory bulb, 2; septum, 3; ventricle 3v, 4; hippocampus, 5; cerebral cortex white matter, 6; cerebral cortex gray-white matter, 7; thalamus, 8; hypothalamus, 9; midbrain, 10; ventricle 4v, 11; ventricle 4v, 12; choroid plexus 4v, 13; cerebellar nuclei, 14; cerebellar cortex, 15; pons, 16; medulla oblongata. The right panel shows the quantification of the image in the left panel.

[0243] Figure 18 shows that region-specific inhibition (KD) by the exemplary compounds provided herein is due to region-specific delivery of the exemplary compounds provided. Region-specific delivery focuses on important brain disease regions and inhibition (KD) is induced by the focused delivery of the exemplary compounds provided herein.

[0244] Figure 19 shows that the region-specific delivery of the exemplary compounds provided herein is due to region-specific energy consumption. Energy consumption by area shows different patterns, with relatively high consumption seen in the regions of the cortex, hippocampus, and cerebellum, and more delivery and inhibition of CNS-SAMiRNA™ observed. Upper panel, region-based 18-fluorodeoxyglucose (FDG) uptake positron emission tomography (PET) quantification. SUV, standardized uptake value; Cort, cortex; Hypo, hypothalamus; STR, striatum; HC, hippocampus; cBS, caudal brainstem; Cere, cerebellum; mean with SEM. Lower panel, glutamate metabolite analysis by mouse brain region using LC-MS / MS.

[0245] Figure 20 shows that the proof-of-concept (PoC) study of the exemplary CNS platform provided herein confirms delivery to important Alzheimer's disease (AD) regions in the deep brain and efficacy in important AD proteins. Alzheimer's disease often begins in the hippocampus and its surroundings. Thus, one of the first prominent symptoms is memory loss.

[0246] Figure 21 shows that the proof-of-concept (PoC) study of the exemplary CNS platform provided herein confirms delivery to important AD regions in the deep brain and efficacy in important AD proteins. Alzheimer's disease is most commonly associated with the accumulation of Aβ and tau. Notable pathways include BACE-1 for Aβ, and MAPT for tau and phosphorylated tau.

[0247] Figures 22A-22D show the results of primary qPCR screening for human BACE1 targets (593 species) (Figure 22A), human MAPT targets (443 species) (Figure 22B), mouse Bace1 targets (42 species) (Figure 22C), and mouse Mapt targets (126 species) (Figure 22D).

[0248] Figures 22E - 22H show the results of secondary qPCR screening for 12 human BACE1 targets (Figure 22E), 12 human MAPT targets (Figure 22F), 19 mouse Bace1 targets (Figure 22G), and 12 mouse Mapt targets (Figure 22H).

[0249] Figure 22I shows that exemplary embodiments of the compounds provided herein using the exemplary CNS platform provided herein, the BACE1 - MAPT siRNA cocktail, target both Aβ and tau, two representative genes of Alzheimer's disease, and knockdown of the target genes is confirmed.

[0250] Figure 23 shows that BACE1 knockdown by Glut - SAMiRNA targeting BACE1 prevents the accumulation of Aβ peptide in CA1 of the deep - brain hippocampus and the uncinate gyrus.

[0251] Figure 24 shows that MAPT knockdown by Glut - SAMiRNA targeting MAPT results in approximately 70% tau peptide accumulation in the uncinate gyrus and prevents the phosphorylation of tau protein.

[0252] Figure 25 shows that phosphorylated tau is effectively regulated as a result of tau protein inhibition via the MAPT knockdown pathway.

[0253] Figure 26 shows that suppression of key AD - related genes improves the cognitive behavior of mice to normal levels (n = 10). Left panel, the Y - maze spontaneous alternation test is useful for the evaluation of hippocampal damage, quantification of cognitive deficits, and evaluation of the effects of drugs on cognition. Right graph, SAMiRNA™ candidates restored the cognitive deficits of AD mice to normal levels.

[0254] Figure 27 shows that the toxicity evaluation of the exemplary CNS platform provided herein during 4 - week repeated IV administration showed no systemic toxicity.

[0255] Figure 28 shows that the toxicity assessment of the exemplary CNS platform provided herein during 4 weeks of repeated IV administration demonstrated minimal hepatotoxicity as evaluated by the alkaline phosphatase (ALP) levels in the serum of 3xTg mice.

[0256] Figure 29 shows that the toxicity assessment of the exemplary CNS platform provided in this specification during 4 weeks of repeated IV administration indicated minimal hepatotoxicity as evaluated by the alanine aminotransferase (ALT) levels and aspartate aminotransferase (AST) levels in the serum of 3xTg mice.

[0257] Figure 30 shows that the toxicity assessment of the exemplary CNS platform provided herein during 4 weeks of repeated IV administration indicated minimal hepatotoxicity as evaluated by the total bilirubin (T-bil) levels and ammonia (NH3) levels in the serum of 3xTg mice.

[0258] Figure 31 shows that the toxicity assessment of the exemplary CNS platform provided herein during 4 weeks of repeated IV administration did not show nephrotoxicity as evaluated by the lactate (Lac) levels in the serum of 3xTg mice.

[0259] Figure 32 shows that the toxicity assessment of the exemplary CNS platform provided in this specification during 4 weeks of repeated IV administration did not show nephrotoxicity as evaluated by the blood urea nitrogen (BUN) levels and creatinine (Crea) levels.

[0260] Figure 33 shows that it was confirmed that the exemplary CNS platform did not affect lipid metabolism by 4 weeks of repeated IV administration as evaluated by the lipase (Lip) levels in the serum of 3×Tg mice.

[0261] Figure 34 shows that an exemplary CNS platform was confirmed not to affect lipid metabolism by repeated IV administration for 4 weeks, as evaluated by high-density lipoprotein (HDL) levels and low-density lipoprotein (LDL) levels in the serum of 3xTg mice.

[0262] Figure 35 shows that an exemplary CNS platform was confirmed not to affect lipid metabolism by repeated IV administration for 4 weeks, as evaluated by total cholesterol (T-Chol) levels and triglyceride (TG) levels in the serum of 3xTg mice.

[0263] Figure 36 shows that an exemplary CNS platform was confirmed not to affect calcium homeostasis by repeated IV administration for 4 weeks, as evaluated by Ca levels and P levels in the serum of 3xTg mice.

[0264] Figure 37 shows that the biodistribution of the exemplary CNS platform provided herein shows significant delivery to the brain (1.4% injected dose (ID) / g brain), as well as to the liver and kidneys. In some embodiments, similar to transferrin, the glucose receptor also shows some off-target effects but has the significant advantage of excellent delivery by blood glucose monitoring. In some embodiments, the selection of the target gene can be important for the safety and efficacy of therapeutic development.

[0265] Figures 38A - 38C show the effect of the exemplary compound SRN - 008 (a compound containing Glut - SAMiRNA targeting BACE1 and MAPT) provided herein on cognitive decline in 3xTg mice. The Y - maze test was performed 24 hours after the final administration. Figure 38A is a scheme showing an exemplary study design. Figure 38B shows spontaneous alternations, and Figure 38C shows total arm entries during the measured 8 - minute session. The vehicle group was treated with PBS. Values are expressed as mean ± S.E.M. #p < 0.05 indicates a significant difference compared to vehicle - treated B6129F1 / J mice, and *p < 0.05 indicates a significant difference compared to vehicle - treated 3xTg mice.

[0266] Figures 39A - 39F show the effect of treatment with the exemplary compound SRN - 008 on Aβ, human tau, and phosphorylated tau accumulation in the CA1 and entorhinal cortex of 3×Tg mice. Figures 39A and 39B show that the 4G8 - positive area was significantly decreased in the CA1 (Figure 39A) and entorhinal cortex (Figure 39B) of SRN - 008 - treated 3xTg mice compared to the control. Figures 39C and 39D show that the HT7 - positive area was significantly decreased in the CA1 (Figure 39C) and entorhinal cortex (Figure 39D) of SRN - 008 - treated 3xTg mice compared to the control. Figures 39E and 39F show that the AT8 - positive area was significantly decreased in the CA1 (Figure 39E) and entorhinal cortex (Figure 39F) of SRN - 008 - treated 3xTg mice compared to the control. Values are expressed as mean ± S.E.M. Scale bar = 50μm ***p < 0.001 indicates a significant difference compared to vehicle - treated 3xTg mice.

[0267] Figures 40A - 40F show exemplary linkages or linkages and exemplary compounds comprising linkages or linkages. Figure 40A shows an exemplary linker - NH(CH2)nCONH - CH2 - CH(OH) - CH2 -, and Figure 40B shows an exemplary embodiment of a compound provided herein. In some embodiments, the N - linker substitutes the OH group at the C6 position of glucose. Figure 40C shows an exemplary linker hexaethylene glycol, and Figure 40D shows an exemplary embodiment of a compound provided herein. Figure 40E shows an exemplary bond, an ether bond where R and R’ represent any alkyl or aryl substituent, and Figure 40F shows an exemplary embodiment of a compound provided herein. In some embodiments, since the OH groups at the C1, C3, and C4 positions of glucose may be essential for the interaction with GLUT1, glucose is introduced via an ether bond at the C6 position to maintain the binding ability to GLUT1. In some embodiments, an exemplary embodiment of the compounds provided herein is a self - assembling supramolecular nanocarrier having a surface characterized by appropriately configured glucose. In some embodiments, a PEG - poly(α,β - aspartic acid) block copolymer (PEG - PAsp) (Gluc(6) - PEG - PAsp) in which glucose is conjugated to the α - terminus of the PEG segment via a bond with the C6 - O moiety.

[0268] Figures 41A - 41C represent immunocytochemistry (ICC) results confirmed by confocal imaging, showing the improved cellular uptake efficiency of glu - SAMiRNA - cy5 compared to SAMiRNA - cy5 in the A549 lung cancer cell line as a function of treatment time. A representative image is shown in Figure 41A. Figure 41B shows a quantified fluorescence graph from five randomly selected regions at 1 hour. Figure 41C shows a quantified fluorescence graph from five randomly selected regions at 20 hours.

[0269] Figure 42 shows an IC 50 graph obtained from RT - qPCR analysis, confirming that the gene inhibition effect of glu - SAMiRNA is enhanced compared to SAMiRNA in the A549 lung cancer cell line.

[0270] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Detailed description

[0271] Unless otherwise defined herein, all technical and scientific terms used in this embodiment shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In general, the nomenclature used in this disclosure is well known and commonly used in the art.

[0272] Definitions As used herein, unless otherwise specified, the singular forms include the plural forms. It should be noted that as used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise.

[0273] As used herein, the term "or" means "and / or" unless otherwise specified. Further, the term "including" and other forms such as "include", "includes", and "included" are not limiting.

[0274] As used herein, references to "some embodiments", "an embodiment", "one embodiment", or "another embodiment" in this specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least some, but not necessarily all, embodiments of the present disclosure.

[0275] As used herein, the terms "comprising" (and any form of comprising such as "comprise" and "comprises"), "having" (any form of having such as "have" and "has"), "including" (any form of including such as "includes" and "include") or "containing" (any form of containing such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any embodiment discussed herein is contemplated to be implementable with respect to any method or composition of the present disclosure, and vice versa. Further, the compositions of the present disclosure can be used to achieve the methods of the present disclosure.

[0276] As used herein, the term "about" with respect to a reference numerical value and its grammatical equivalents can include the numerical value itself and a range of values from plus or minus 10% of that numerical value. For example, an amount "about 10" can include 10 and any amount from 9 to 11. For example, the term "about" with respect to a reference numerical value can also include values in the range of plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that value.

[0277] As used herein, the terms "subject", "patient", and "individual" include animals (e.g., vertebrates, amphibians, fish, mammals, cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, primates (e.g., chimpanzees, gorillas, and humans)) that can be afflicted with the diseases or disorders described herein. A "subject" may also be a cell, a population of cells, a tissue, an organ or an organism, preferably a human and its components. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is an animal cell. The subject is preferably a mammal in need of such treatment, e.g., a subject diagnosed with, at risk of, or having a predisposition to develop the disorders described herein. The mammal can be, for example, any mammal, such as a human, a primate, a mouse, a rat, a dog, a cat, a horse, as well as domestic animals or animals raised for food consumption, such as cows, sheep, pigs, chickens and goats. In a preferred embodiment, the mammal is a human.

[0278] As used herein, "control" or "standard control" refers to a reference, usually a sample, measurement, or value that functions as a reference for comparison to a test sample, measurement, or value. For example, a test sample can be taken from a subject having a given disease and compared to a known normal (disease-free) individual (e.g., the subject of a standard control). A standard control can also represent an average measurement or value collected from a population of similar individuals (e.g., the subject of a standard control) who do not have a given disease (i.e., the standard control subject), e.g., healthy individuals having a similar medical background, the same age, weight, etc. Standard control values can also be obtained from the same individual, e.g., from a sample previously obtained from a patient before the onset of the disease. For example, a control can be devised for comparing therapeutic benefits based on pharmacological data (e.g., half-life) or treatment means (e.g., comparison of side effects). Controls are also useful for determining the significance of data. For example, if the value of a given parameter varies widely in the control, the variation in the test sample is not considered significant. One of ordinary skill in the art will recognize that standard controls can be designed for the evaluation of any number of parameters (e.g., RNA level, protein level, specific cell type, specific body fluid, specific tissue, brain tissue, etc.).

[0279] As used herein, the terms "prevent", "preventing", and "prevention" refer to a decrease in the occurrence of the condition of a disease or disorder described herein in a subject. Prevention can, for example, be the complete absence of the condition of a disease or disorder described herein in a subject. Prevention can be partial, such that the occurrence of the condition of a disease or disorder described herein in a subject is less than would have occurred without the present disclosure.

[0280] As used herein, the terms "treating," "treatment," and "treat" are used herein to generally mean obtaining a desired pharmacological and / or physiological effect. The effect can be prophylactic in terms of preventing or partially preventing a disease, its symptoms or condition, and / or therapeutic in terms of partially or completely curing a disease, condition, symptom or adverse effect thereof. As used herein, the term "treatment" includes any treatment of a disease in a mammal, particularly a human, and includes (a) preventing a disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., alleviating or improving the disease and / or its symptoms or condition. The present disclosure relates to treating a patient suffering from a disease or disorder described herein. The term "prevention" is used herein to refer to the means(s) taken for preventing or partially preventing a disease or condition.

[0281] As used herein, "treating or preventing a disease or disorder" means ameliorating any condition, symptom, or sign associated with the disorder or disease, including, for example, neuronal cell death, inflammation, and movement disorders, either before or after its occurrence. For example, alleviating the symptoms of a disorder may include reducing the visible area of neuronal cell death as compared to an untreated control. The degree of such reduction or prevention, as compared to an equivalent untreated control, is at least 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% when measured by any standard technique. A patient being treated for a disease or disorder described herein, such as a neurological disease or cancer, is a patient diagnosed by a physician as having such a condition. The diagnosis can be by any appropriate means. Diagnosis and monitoring can include, for example, detecting the presence of damaged or dead neurons in a biological sample (e.g., a tissue biopsy, a blood test, or a urine test), detecting the presence of plaques, detecting the level of surrogate markers of neuropathy in a biological sample, or detecting symptoms or signs associated with neuropathy. Diagnosis and monitoring can include, for example, detecting the presence of cancer cells in a biological sample (e.g., a tissue biopsy, a blood test, or a urine test), detecting the presence of a tumor, detecting the level of surrogate markers of cancer in a biological sample, or detecting symptoms or signs associated with cancer. A patient in whom the onset of neuropathy or cancer has been prevented may or may not have received such a diagnosis. One of ordinary skill in the art will understand that these patients may have been subjected to the same standard tests as described above, or may have been identified as high-risk patients due to the presence of one or more risk factors (e.g., family history or genetic predisposition) without testing.

[0282] As used herein, the terms "disease" and "disorder" are used interchangeably.

[0283] As used herein, the terms "blood-brain barrier" and "BBB" are used interchangeably and refer to a permeability barrier that closely regulates and severely restricts the exchange between blood and brain tissue. In some embodiments, the blood-brain barrier components include endothelial cells that form the innermost lining of all blood vessels, high-density junctions between adjacent endothelial cells that are structurally related to the BBB, the basement membrane of the endothelial cells, and the expanded foot processes of nearby astrocytes that cover substantially all of the outer surface of the exposed blood vessels.

[0284] As used herein, the phrase "therapeutically effective amount" refers to the amount of an agent, such as a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, necessary to treat, ameliorate, or prevent a target disease or condition. In some embodiments, a "therapeutically effective amount" is an amount of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein that provides a beneficial effect or reduces a detrimental, non-beneficial event in an individual to whom the composition is administered. The exact dosage depends on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).

[0285] As used herein, the term "inhibitory oligonucleotide molecule" refers to a nucleic acid molecule capable of inhibiting the expression and / or activity of a target nucleic acid molecule, such as an RNA molecule. Exemplary inhibitory oligonucleotide molecules include, but are not limited to, RNAi agents, shRNA, siRNA, miRNA, amiRNA, and antisense oligonucleotide molecules. In some embodiments, the inhibitory oligonucleotide molecule comprises a region that is substantially complementary to at least a portion of a target nucleic acid molecule, such as a target mRNA transcript.

[0286] As used herein, the term "RNA interference (RNAi)" refers to a biological process in which an RNA molecule is involved in the sequence-specific inhibition of gene expression and / or activity by double-stranded RNA through translational or transcriptional repression.

[0287] As used herein, the term "RNAi agent" refers to an agent that induces or promotes RNA interference. In some embodiments, the RNAi agent induces or promotes RNA interference in vivo, in vitro, in cells, tissues, or a subject.

[0288] As used herein, the term "shRNA," also known as "short hairpin RNA" or "small hairpin RNA," refers to an artificial RNA molecule having a tight hairpin turn that can be used to silence the expression and / or activity of a target gene through RNA interference.

[0289] As used herein, the term "siRNA," also known as "small interfering RNA" or "short interfering RNA" or "silencing RNA," refers to a class of double-stranded RNA that is initially a non-coding RNA molecule, typically 20-24 (usually 21) base pairs in length and that operates within the RNA interference pathway. In some embodiments, the siRNA inhibits the expression and / or activity of a specific gene having a complementary nucleotide sequence by degrading the mRNA post-transcriptionally and preventing translation.

[0290] As used herein, the terms "miRNA" or "microRNA" or "miR" refer to small single-stranded non-coding RNA molecules containing 21-23 nucleotides that are involved in RNA silencing and post-transcriptional regulation of gene expression. In some embodiments, miRNAs are found in plants, animals, and some viruses. As used herein, the term "amiRNA" refers to artificial microRNA.

[0291] As used herein, "L i " or "L j " refers to a polysaccharide containing "i" or "j" monosaccharides. For example, L2 refers to a disaccharide and L3 refers to a trisaccharide.

[0292] As used herein, the term "antisense oligonucleotide molecule" refers to a single strand of DNA or RNA that is complementary to a selected sequence. In some embodiments, antisense oligonucleotide molecules prevent the protein translation of those messenger RNA strands by binding to specific messenger RNA strands in a process called hybridization. In some embodiments, antisense oligonucleotide molecules can be used to target specific complementary (coding or non-coding) RNAs.

[0293] As used herein, the term "isolated" refers to a material that has been changed or removed from its natural state or its original environment or natural surroundings. For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, while the same polynucleotide or polypeptide separated from some or all of the coexisting substances in the natural system by human intervention is isolated. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)) or polypeptide does not contain the genes / nucleic acids or sequences / amino acids that are adjacent to it in its natural state.

[0294] The term "operably linked" refers to a functional linkage between two parts or two nucleotide sequences. For example, if a first part or a first nucleotide sequence is in a functional relationship with a second part or a second nucleotide sequence, the first part or the first nucleotide sequence is operably linked to the second part or the second nucleotide sequence.

[0295] As used herein, the terms "nucleic acid", "nucleotide", "polynucleotide", or "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide can be either single-stranded or double-stranded, and in the case of single-stranded, it can be either the coding strand or the non-coding (antisense) strand. A polynucleotide can include modified nucleotides such as methylated nucleotides and nucleotide analogs. A nucleic acid can be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semi-synthetic or synthetic origin that is not naturally occurring or is linked to another polynucleotide in a non-natural sequence. The following abbreviations for commonly occurring nucleobases are used. "A" refers to adenosine, "C" refers to cytosine, "G" refers to guanosine, "T" refers to thymidine, and "U" refers to uridine.

[0296] As used herein, the terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses modified amino acid polymers. For example, any other operation such as formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with a labeling component. A polypeptide can be isolated from a natural source, produced by recombinant techniques from a eukaryotic or prokaryotic host, or be the product of synthetic procedures.

[0297] As used herein, the terms "identity" or "homology" are used interchangeably. To determine the percent identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. The molecule is identical at that position if the position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap.The comparison of sequences and determination of the percent identity between two sequences can be accomplished using a mathematical algorithm, e.g., the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm incorporated into the GAP program of the GCG software package; using either the Blossum 62 matrix or the PAM250 matrix with gap weights of 16, 14, 12, 10, 8, 6 or 4 and length weights of 1, 2, 3, 4, 5 or 6; using the GAP program within the GCG software package with the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70 or 80 and length weights of 1, 2, 3, 4, 5 or 6; using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) incorporated into the ALIGN program (version 2.0) (with a gap length penalty of 12 and a gap penalty of 4 in the PAM120 weighted residue table); or using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10 (score = 100, word length = 12 for the NBLAST program, or score = 50, word length = 3 for the XBLAST program).

[0298] As used herein, the terms "analog" or "functional analog" refer to a molecule that contains a substantially similar structure and can have one or more activities of the reference molecule. In some embodiments, the functional analog has at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the activity of the reference molecule.

[0299] As used herein, the terms "monosaccharide" or "simple sugar" or "sugar" refer to the simplest form of a sugar and the most basic unit from which all carbohydrates are built.

[0300] As used herein, the term "SAMiRNA™" refers to self-assembling micelle inhibitory RNA, which is a nanoparticle-based siRNA.

[0301] In some embodiments, SAMiRNA™ has the formula 1: A-X-R-Y-B [Formula 1] (wherein, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y each independently represent a simple covalent bond or a linker-mediated covalent bond, and R refers to a double-stranded oligonucleotide comprising a sense strand and an antisense strand containing a sequence complementary thereto) and has the structure of.

[0302] As used herein, the terms "CNS platform" or "brain platform" are used interchangeably and refer to the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, wherein a ligand molecule of a glucose transporter (GLUT) or a functional analog thereof is covalently linked to the hydrophilic or hydrophobic moiety of a self-assembled micelle oligonucleotide molecule, such as SAMiRNA™, and blood-brain barrier penetration and / or brain delivery of the CNS platform or brain platform is increased compared to a self-assembled micelle oligonucleotide molecule that does not contain a ligand molecule or a functional analog thereof for the linked GLUT.

[0303] GLUT ligand, oligonucleotide compound comprising hydrophilic and hydrophobic moieties In one aspect, particularly Formula 16: A-X-R-Y-B Formula 16 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are, independently, a covalent bond or a first linker) A compound comprising the structure of A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker to the terminus of A, the terminus of B, or a combination thereof The second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2- Compounds are provided herein that modulate the expression level and / or activity level of a target molecule

[0304] In one embodiment, particularly Formula 16: A-X-R-Y-B Formula 16 (wherein R is an oligonucleotide molecule A is a hydrophilic moiety B is a hydrophobic moiety X and Y are, independently, a covalent bond or a first linker A compound comprising the structure of A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked to the terminus of A, the terminus of B, or a combination thereof

[0305] In some embodiments, the compound is of Formula 16: A-X-R-Y-B Formula 16 (wherein R is an oligonucleotide molecule A is a hydrophilic moiety B is a hydrophobic moiety X and Y are, independently, a covalent bond or a first linker) comprising the structure of A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker to the terminus of A, the terminus of B, or a combination thereof The second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-.

[0306] In one aspect, Formula 16: A-X-R-Y-B Formula 16 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A compound comprising the structure of, A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, R is a compound that regulates the expression level and / or activity level of a target molecule. Compounds are provided herein. In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical formula

Chemical formula

[0307] In some embodiments, the second linker is any one listed in Table 7.

[0308] In another aspect, Formula 16: A-X-R-Y-B Formula 16 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A compound comprising the structure of A ligand molecule or a functional analog thereof for a glucose transporter (GLUT) is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, and compounds are provided herein. In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical formula

Chemical formula

[0309] In some embodiments, the second linker is any one listed in Table 7.

[0310] In some embodiments, R reduces or inhibits the expression and / or activity of the target molecule. In some embodiments, R reduces or inhibits the expression of the target molecule. In some embodiments, R reduces or inhibits the activity of the target molecule.

[0311] In some embodiments, R reduces or inhibits the expression of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% as compared to the expression of the target molecule in a subject tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, R reduces or inhibits the activity of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% as compared to the expression of the target molecule in a subject tissue, organ, cell or subject not treated with a compound as provided herein.

[0312] In some embodiments, the compound has the formula 14 or formula 15: (L i )-A-X-R-Y-B Formula 14, A-X-R-Y-B-(L j ) Formula 15 (wherein L is a ligand molecule for GLUT or a functional analog thereof, i and j are independently integers from 0 to 10, when i is 0, j is an integer from 1 to 10, and when j is 0, i is an integer from 1 to 10) and includes the structure of.

[0313] In some embodiments, i is an integer from 0 to 10. In some embodiments, i is an integer from 0 to 100, 0 to 95, 0 to 90, 0 to 85, 0 to 80, 0 to 75, 0 to 70, 0 to 70, 0 to 65, 0 to 60, 0 to 55, 0 to 50, 0 to 45, 0 to 40, 0 to 35, 0 to 30, 0 to 25, 0 to 20, 0 to 19, 0 to 18, 0 to 17, 0 to 16, 0 to 15, 0 to 14, 0 to 13, 0 to 12, 0 to 11, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, or 0 to 2. In some embodiments, i is an integer from 1 to 100, 2 to 100, 3 to 100, 4 to 100, 5 to 100, 6 to 100, 7 to 100, 8 to 100, 9 to 100, 10 to 100, 11 to 100, 12 to 100, 13 to 100, 14 to 100, 15 to 100, 16 to 100, 17 to 100, 18 to 100, 19 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100. In some embodiments, i is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0314] In some embodiments, j is an integer from 0 to 10. In some embodiments, j is an integer from 0 to 100, 0 to 95, 0 to 90, 0 to 85, 0 to 80, 0 to 75, 0 to 70, 0 to 70, 0 to 65, 0 to 60, 0 to 55, 0 to 50, 0 to 45, 0 to 40, 0 to 35, 0 to 30, 0 to 25, 0 to 20, 0 to 19, 0 to 18, 0 to 17, 0 to 16, 0 to 15, 0 to 14, 0 to 13, 0 to 12, 0 to 11, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, or 0 to 2. In some embodiments, j is an integer from 1 to 100, 2 to 100, 3 to 100, 4 to 100, 5 to 100, 6 to 100, 7 to 100, 8 to 100, 9 to 100, 10 to 100, 11 to 100, 12 to 100, 13 to 100, 14 to 100, 15 to 100, 16 to 100, 17 to 100, 18 to 100, 19 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100. In some embodiments, j is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0315] In some embodiments, i is an integer of 0 and j is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, i is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 and j is an integer of 0.

[0316] In some embodiments, the ligand molecule for GLUT is a sugar. In some embodiments, the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose. In some embodiments, the ligand molecule for GLUT is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, trehalose, and urate.

[0317] In some embodiments, GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14. In some embodiments, GLUT is selected from any one of the GLUTs listed in Tables 3, 4, and 5. In some embodiments, GLUT includes any recombinant or naturally occurring form of a GLUT or a variant or homolog thereof (e.g., having at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity) that has or maintains GLUT activity. In some aspects, the variant or homolog has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50-, 100-, 150- or 200 -amino acid contiguous portion) compared to a naturally occurring GLUT. In some embodiments, GLUT is substantially identical to the protein identified by the UniProt reference number listed in Table 3, or a variant or homolog having substantial identity thereto.

[0318] In some embodiments, the ligand molecule for GLUT is fructose, and GLUT is selected from the group consisting of GLUT2, GLUT5, GLUT7, GLUT8, GLUT9, GLUT11, and GLUT12. In some embodiments, the ligand molecule for GLUT is galactose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, and GLUT14. In some embodiments, the ligand molecule for GLUT is glucose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, and GLUT12. In some embodiments, the ligand molecule for GLUT is mannose, and GLUT is selected from the group consisting of GLUT1, GLUT2, GLUT3, and GLUT4. In some embodiments, the ligand molecule for GLUT is xylose, and GLUT is GLUT3. In some embodiments, the ligand molecule for GLUT is dehydroascorbic acid, and GLUT is GLUT4. In some embodiments, the ligand molecule for GLUT is trehalose, and GLUT is GLUT8. In some embodiments, the ligand molecule for GLUT is uric acid, and GLUT is GLUT9. In some embodiments, the ligand molecule for GLUT is any one selected from the ligands listed in Table 3, and GLUT is the corresponding GLUT listed in Table 3.

[0319] In some embodiments, R is a double-stranded oligonucleotide molecule or a single-stranded oligonucleotide molecule. In some embodiments, R is an inhibitory oligonucleotide molecule. In some embodiments, the inhibitory oligonucleotide molecule reduces or inhibits the expression and / or activity of the target molecule. In some embodiments, the target molecule is a transcript of a gene associated with a disease.

[0320] In some embodiments, the target molecule is a transcript of a gene associated with a neurological disorder. In some embodiments, the target molecule is overexpressed or activated in a patient having a neurological disorder. In some embodiments, the target molecule is a transcript of a gene associated with Alzheimer's disease. In some embodiments, the target molecule is a transcript of a gene disclosed in Table 6A. In some embodiments, the target molecule is a transcript of a gene associated with Parkinson's disease. In some embodiments, the target molecule is a transcript of a gene disclosed in Table 6B. In some embodiments, the target molecule is a transcript of a gene associated with Huntington's disease. In some embodiments, the target molecule is a transcript of a gene disclosed in Table 6C. In some embodiments, the target molecule is a transcript of a gene associated with multiple sclerosis. In some embodiments, the target molecule is a transcript of a gene disclosed in Table 6D. In some embodiments, the target molecule is a transcript of a gene associated with spinal cord injury. In some embodiments, the target molecule is a transcript of a gene disclosed in Table 6E.

[0321] In some embodiments, the target molecule is any one transcript selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA.

[0322] In some embodiments, the target molecule is a transcript of a gene associated with cancer. In some embodiments, the target molecule is overexpressed or activated in cancer cells.

[0323] In some embodiments, the inhibitory oligonucleotide molecule is siRNA, shRNA, miRNA, amiRNA, an antisense oligonucleotide molecule, an RNAi agent, or any combination thereof. In some embodiments, R is a double-stranded oligonucleotide molecule comprising a sense strand and an antisense strand comprising a sequence complementary to the sense strand. In some embodiments, R is a double-stranded oligonucleotide comprising a DNA / DNA, DNA / RNA or RNA / RNA hybrid. In some embodiments, R comprises a DNA / RNA duplex.

[0324] In some embodiments, the sense strand or the antisense strand is 19 to 31 nucleotides in length. In some embodiments, the sense strand or the antisense strand is 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, or 1 to 10 nucleotides in length. In some embodiments, the sense strand or the antisense strand is 5 to 100, 10 to 100, 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 nucleotides in length. In some embodiments, the sense strand or the antisense strand is 5 to 45, 10 to 40, 15 to 35, 16 to 34, 17 to 33, 18 to 32, 19 to 31, 20 to 30, 21 to 29, 22 to 28, 23 to 27, 24 to 26 nucleotides in length. In some embodiments, the sense strand or the antisense strand is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length. In some embodiments, the sense strand or the antisense strand comprises 19 to 31 nucleotides. In some embodiments, the sense strand or the antisense strand comprises 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, or 1 to 10 nucleotides. In some embodiments, the sense strand or the antisense strand comprises 5 to 100, 10 to 100, 15 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 nucleotides.In some embodiments, the sense strand or the antisense strand comprises 5 to 45 nucleotides, 10 to 40 nucleotides, 15 to 35 nucleotides, 16 to 34 nucleotides, 17 to 33 nucleotides, 18 to 32 nucleotides, 19 to 31 nucleotides, 20 to 30 nucleotides, 21 to 29 nucleotides, 22 to 28 nucleotides, 23 to 27 nucleotides, 24 to 26 nucleotides. In some embodiments, the sense strand or the antisense strand comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides.

[0325] In some embodiments, at least one phosphate group is linked to the 5' end of the antisense strand.

[0326] In some embodiments, the compound has the formula 2: A-X-S-Y-B AS Formula 2 (wherein S is the sense strand and AS is the antisense strand) and includes the structure of.

[0327] In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 50 oligonucleotides, 10 to 40 oligonucleotides, or 15 to 30 oligonucleotides.

[0328] In some embodiments, R is an antisense oligonucleotide molecule consisting of 1 to 200 oligonucleotides, 5 to 200 oligonucleotides, 10 to 200 oligonucleotides, 15 to 200 oligonucleotides, 20 to 200 oligonucleotides, 25 to 200 oligonucleotides, 30 to 200 oligonucleotides, 35 to 200 oligonucleotides, 40 to 200 oligonucleotides, 45 to 200 oligonucleotides, 50 to 200 oligonucleotides, 55 to 200 oligonucleotides, 60 to 200 oligonucleotides, 65 to 200 oligonucleotides, 70 to 200 oligonucleotides, 75 to 200 oligonucleotides, 80 to 200 oligonucleotides, 85 to 200 oligonucleotides, 90 to 200 oligonucleotides, 95 to 200 oligonucleotides, 100 to 200 oligonucleotides, 105 to 200 oligonucleotides, 110 to 200 oligonucleotides, 115 to 200 oligonucleotides, 120 to 200 oligonucleotides, 125 to 200 oligonucleotides, 130 to 200 oligonucleotides, 135 to 200 oligonucleotides, 140 to 200 oligonucleotides, 145 to 200 oligonucleotides, 150 to 200 oligonucleotides, 155 to 200 oligonucleotides, 160 to 200 oligonucleotides, 165 to 200 oligonucleotides, 160 to 200 oligonucleotides, 175 to 200 oligonucleotides, 180 to 200 oligonucleotides, 185 to 200 oligonucleotides, 190 to 200 oligonucleotides, or 195 to 200 oligonucleotides.In some embodiments, R is an antisense oligonucleotide molecule consisting of 1 to 195 oligonucleotides, 1 to 190 oligonucleotides, 1 to 185 oligonucleotides, 1 to 180 oligonucleotides, 1 to 175 oligonucleotides, 1 to 170 oligonucleotides, 1 to 165 oligonucleotides, 1 to 160 oligonucleotides, 1 to 155 oligonucleotides, 1 to 150 oligonucleotides, 1 to 145 oligonucleotides, 1 to 140 oligonucleotides, 1 to 135 oligonucleotides, 1 to 130 oligonucleotides, 1 to 125 oligonucleotides, 1 to 120 oligonucleotides, 1 to 115 oligonucleotides, 1 to 110 oligonucleotides, 1 to 105 oligonucleotides, 1 to 100 oligonucleotides, 1 to 95 oligonucleotides, 1 to 90 oligonucleotides, 1 to 85 oligonucleotides, 1 to 80 oligonucleotides, 1 to 75 oligonucleotides, 1 to 70 oligonucleotides, 1 to 65 oligonucleotides, 1 to 60 oligonucleotides, 1 to 55 oligonucleotides, 1 to 50 oligonucleotides, 1 to 45 oligonucleotides, 1 to 40 oligonucleotides, 1 to 35 oligonucleotides, 1 to 30 oligonucleotides, 1 to 25 oligonucleotides, 1 to 20 oligonucleotides, 1 to 15 oligonucleotides, or 1 to 10 oligonucleotides. In some embodiments, R is an antisense oligonucleotide molecule consisting of 5 to 45 oligonucleotides, 10 to 40 oligonucleotides, 15 to 30 oligonucleotides or 20 to 25 oligonucleotides.In some embodiments, R is an antisense oligonucleotide molecule consisting of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 oligonucleotides.

[0329] In some embodiments, R is DNA, RNA, or a combination thereof. In some embodiments, R includes DNA / DNA, RNA / RNA, or DNA / RNA hybrids.

[0330] In some embodiments, R includes backbone modifications including phosphorothioate linkages, phosphorodiamidate linkages, boranophosphate linkages, methylphosphonate linkages, or any combination thereof.

[0331] In some embodiments, R includes locked nucleic acids, peptide nucleic acids, unlocked nucleic acids, or any combination thereof.

[0332] In some embodiments, R includes a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, a 2'-methyl moiety, a 2'-methoxyl moiety, a 2'-amine moiety, a 2'-O-propyl moiety, a 2'-O-2-methylthioethyl moiety, a 2'-O-3-aminopropyl moiety, a 2'-O-3-dimethylaminopropyl moiety, a 2'-O-N-methylacetamino moiety or a 2'-O-dimethylamidooxyethyl moiety.

[0333] In some embodiments, R includes a modified sugar moiety.

[0334] In some embodiments, the hydrophilic moiety is any one selected from the group consisting of polyethylene glycol (PEG), polyvinylpyrrolidone, and polyoxazoline. In some embodiments, the hydrophilic moiety comprises HEG (hexaethylene glycol). In some embodiments, the hydrophilic moiety is HEG (hexaethylene glycol). In some embodiments, the hydrophilic moiety comprises or consists of hexaethylene glycol-(-PO3 - hexaethylene glycol)3.

[0335] In some embodiments, R includes nucleotide modifications. In some embodiments, modifications include, for example: (a) terminal modifications, such as 5'-terminal modifications (phosphorylation, conjugation, inverse linkage, etc.) and 3'-terminal modifications (conjugation, DNA nucleotides, inverse linkage, etc.); (b) base modifications, such as stabilized bases, destabilized bases, or replacement of bases that form base pairs with an expanded repertoire of partners, removal of bases (abasic nucleotides), or replacement with conjugated bases; (c) sugar modifications (e.g., at the T position or 4' position) or sugar replacement; and (d) backbone modifications including modification or replacement of the phosphodiester bond. In some embodiments, modified nucleotide backbones include, for example, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkyl phosphotriester, methyl and other alkyl phosphonates (including 3'-alkylene phosphonates and chiral phosphonates), phosphinate, phosphoramidate including 3'-aminophosphoramidate and aminoalkyl phosphoramidate, thionophosphoramidate, thionoalkyl phosphonate, thionoalkyl phosphotriester, and boranophosphate having a normal 3'-5' linkage, 2'-5' linkage analogs thereof, and those having an inverted polarity (wherein the pairs of adjacent nucleoside units are linked from 3'-5' to 5'-3' or from 2'-5' to 5'-2'). In some embodiments, various salts, mixed salts, and free acid forms are also included. In some embodiments, modified nucleotide backbones that do not contain a phosphorus atom have a backbone formed by short-chain alkyl or cycloalkyl nucleoside linkages, mixed heteroatom and alkyl or cycloalkyl nucleoside linkages, or one or more short-chain heteroatom or heterocyclic nucleoside linkages.In some embodiments, these include those having morpholino linkages (formed in part from the sugar portion of the nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methyleneformacetyl and thioformacetyl backbones; alkene-containing backbones; sulfamic acid backbones; methyleneimino and methylenehydrazino backbones; sulfonic acid and sulfonamide backbones; amide backbones; others having oligonucleotides with mixed N, O, S and CH2 constituent moieties and heteroatom backbones, particularly -CH2-NH-CH2-, -CH2-N(CH3)-O-CH2- [known as the methylene(methylimino) or MMI backbone], -CH2-O-N(CH3)-CH2-, -CH2-N(CH3)-N(CH3)-CH2-, and -N(CH3)-CH2-CH2- (the natural phosphodiester backbone is represented as -O-P-O-CH2-). In some embodiments, exemplary linkages or linkings, and exemplary compounds containing linkages or linkings are as shown in FIGS. 40A - 40F.

[0336] In some embodiments, for other nucleotide mimetics suitable or contemplated for use herein, both the sugar of the nucleotide unit and the internucleoside linkage, i.e., both backbones, are replaced with novel groups. In some embodiments, the base unit is maintained for hybridization with a suitable nucleic acid target compound. In some embodiments, one such oligomeric compound is a peptide nucleic acid (PNA). In a PNA compound, the sugar backbone of the nucleotide is replaced with an amide-containing backbone, particularly an aminoethylglycine backbone. The nucleobase is retained and is directly or indirectly attached to the azanitrogen atom of the amide portion of the backbone. In some embodiments, an oligonucleotide molecule can also be modified to include one or more locked nucleic acids (LNAs). A locked nucleic acid is a nucleotide having a modified ribose moiety that includes an extra bridge connecting the 2'-carbon and the 4'-carbon. In some embodiments, this structure effectively "locks" the ribose in a 3'-end structural conformation. In some embodiments, the addition of locked nucleic acids to an oligonucleotide molecule can increase stability in serum and reduce off-target effects.

[0337] In some embodiments, a modified nucleotide can also include one or more substituted sugar moieties. In some embodiments, R can include one of the following at the 2'-position: OH; F; O-, S- or N-alkyl; O-, S- or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl (wherein alkyl, alkenyl and alkynyl can be substituted or unsubstituted C l ~C 10 alkyl or C2~C 10 alkenyl and alkynyl). In some embodiments, exemplary suitable modifications include O[(CH2)nO]mCH3, O(CH2)nOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. In some embodiments, R can include one of the following at the 2-position: C l ~C10 Lower alkyl, substituted lower alkyl, aralkyl, aralkyl, O-aralkyl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloaralkyl, aminoalkylamino, polyalkylamino, substituted silyl, nucleotide cleavage group, reporter group, intercalator, group for improving the pharmacokinetic properties of an oligonucleotide molecule, or a group for improving the pharmacodynamic properties of an oligonucleotide molecule, and other substituents having similar properties. In some embodiments, the modification comprises 2'-methoxyethoxy (2'-O-(2-methoxyethyl) or 2'-MOE also known as 2'-O-CH2CH2OCH3), i.e., an alkoxy-alkoxy group. Another exemplary modification includes 2'-dimethylaminooxyethoxy, i.e., the O(CH2)2ON(CH3)2 group also known as 2'-DMAOE, and 2'-dimethylaminoethoxyethoxy (also known as 2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-O-CH2-O-CH2-N(CH2)2, but is not limited thereto.

[0338] In some embodiments, other modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2-OCH2CH2CH2NH2) and 2'-fluoro (2'-F). In some embodiments, similar modifications can also be made at other positions on the nucleotide, particularly at the 3' position of the sugar on the 3' terminal nucleotide or at the 5' position of the 2'-5' linked double-stranded oligonucleotide and the 5' terminal nucleotide. In some embodiments, R can also have a sugar mimetic such as a cyclobutyl moiety instead of a pentofuranosyl sugar.

[0339] In some embodiments, R may also include modifications or substitutions of nucleobases (often simply referred to as "bases" in the art). As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U). In some embodiments, modified nucleobases include other synthetic and natural nucleobases, such as 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyluracil and cytosine, 6-azauracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal, other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine, and 3-deazaguanine and 3-deazaadenine. In some embodiments, these nucleobases may be useful for enhancing the binding affinity of oligonucleotide molecules. In some embodiments, these include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, and 5-methylcytosine substitutions for enhancing nucleic acid duplex stability.

[0340] The preparation of the above modified nucleic acids, backbones and nucleobases is well known in the art.

[0341] In some embodiments, the compound is of formula 7 or formula 8: (A’ m -J) n-X-R-Y-B Formula 7 (J - A’ m ) n -X-R-Y-B Formula 8 (wherein, A’ is a monomer hydrophilic moiety, J is selected from the group consisting of PO3 - , SO3 - and CO2 - , and either connects A’ to each other or connects A’ to X, m is an integer from 1 to 15, n is an integer from 1 to 10, A’ is Compound 1, Compound 2, and Compound 3

Chemical Structure

Chemical Structure

Chemical Structure

[0342] In some embodiments, m is an integer from 1 to 15. In some embodiments, m is an integer from 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, m is an integer from 1 to 100, 2 to 100, 3 to 100, 4 to 100, 5 to 100, 6 to 100, 7 to 100, 8 to 100, 9 to 100, 10 to 100, 11 to 100, 12 to 100, 13 to 100, 14 to 100, 15 to 100, 16 to 100, 17 to 100, 18 to 100, 19 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100. In some embodiments, m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0343] In some embodiments, n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, n is an integer from 1 to 100, 2 to 100, 3 to 100, 4 to 100, 5 to 100, 6 to 100, 7 to 100, 8 to 100, 9 to 100, 10 to 100, 11 to 100, 12 to 100, 13 to 100, 14 to 100, 15 to 100, 16 to 100, 17 to 100, 18 to 100, 19 to 100, 20 to 100, 25 to 100, 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100. In some embodiments, n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0344] In some embodiments, the molecular weight of the hydrophilic moiety is from 200 to 10,000.

[0345] In some embodiments, the molecular weight of the hydrophilic moiety is from 10 to 50,000, from 10 to 45,000, from 10 to 40,000, from 10 to 35,000, from 10 to 30,000, from 10 to 25,000, from 10 to 20,000, from 10 to 15,000, from 10 to 10,000, from 10 to 9,500, from 10 to 9,000, from 10 to 8,500, from 10 to 8,000, from 10 to 7,500, from 10 to 7,000, from 10 to 6,500, from 10 to 6,000, from 10 to 5,500, from 10 to 5,000, from 10 to 4,500, from 10 to 4,000, from 10 to 3,500, from 10 to 3,000, from 10 to 2,500, from 10 to 2,000, from 10 to 1,500, from 10 to 1,000, from 10 to 950, from 10 to 900, from 10 to 850, from 10 to 800, from 10 to 750, from 10 to 700, from 10 to 650, from 10 to 600, from 10 to 550, from 10 to 500, from 10 to 450, from 10 to 400, from 10 to 350, from 10 to 300, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 150, or from 10 to 100. In some embodiments, the molecular weight of the hydrophilic moiety is from 50 to 50,000, from 100 to 50,000, from 150 to 50,000, from 200 to 50,000, from 250 to 50,000, from 300 to 50,000, from 350 to 50,000, from 400 to 50,000, from 450 to 50,000, from 500 to 50,000, from 550 to 50,000, from 600 to 50,000, from 650 to 50,000, from 700 to 50,000, from 750 to 50,000, from 800 to 50,000, from 850 to 50,000, from 900 to 50,000, from 950 to 50,000, from 1,000 to 50,000, from 1,500 to 50,000, from 2,000 to 50,000, from 2,500 to 50,000, from 3,000 to 50,000, from 3,500 to 50,000, from 4,000 to 50,000, from 4,500 to 50,000, from 5,000 to 50,000, from 5,500 to 50,000, from 6,000 to 50,000, from 6,500 to 50,000, from 7,000 to 50,000, from 7,500 to 50,000, from 8,000 to 50,000, from 8,500 to 50,000, from 9,000 to 50,000, from 10,000 to 50,000, from 15,000 to 50,000, from 20,000 to 50,000, from 25,000 to 50,000, from 30,000 to 50,000, from 35,000 to 50,000, from 40,000 to 50,000, or from 45,000 to 50,000.In some embodiments, the molecular weight of the hydrophilic moiety is from 10 to 30,000, from 50 to 25,000, from 100 to 20,000, from 150 to 15,000, from 200 to 10,000, from 250 to 5,000, or from 500 to 1,000.

[0346] In some embodiments, the hydrophobic moiety is any one selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycols, unsaturated or saturated C 12 ~C 50 , diacyl phosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols, and tocotrienols. In some embodiments, the steroid derivative is any one selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cotestanyl formate, and cholestanyl amine. In some embodiments, the glyceride derivative is any one selected from the group consisting of monoglycerides, diglycerides, and triglycerides.

[0347] In some embodiments, the molecular weight of the hydrophobic moiety is from 250 to 1,000. In some embodiments, the molecular weight of the hydrophobic moiety is from 10 to 5,000, from 50 to 5,000, from 100 to 5,000, from 150 to 5,000, from 200 to 5,000, from 250 to 5,000, from 300 to 5,000, from 350 to 5,000, from 400 to 5,000, from 450 to 5,000, from 500 to 5,000, from 550 to 5,000, from 600 to 5,000, from 650 to 5,000, from 700 to 5,000, from 750 to 5,000, from 800 to 5,000, from 850 to 5,000, from 900 to 5,000, from 1,000 to 5,000, from 1,500 to 5,000, from 2,000 to 5,000, from 2,500 to 5,000, from 3,000 to 5,000, from 3,500 to 5,000, from 4,000 to 5,000, or from 4,500 to 5,000. In some embodiments, the molecular weight of the hydrophobic moiety is from 10 to 4,500, from 10 to 4,000, from 10 to 3,500, from 10 to 3,000, from 10 to 2,500, from 10 to 2,000, from 10 to 1,500, from 10 to 1,000, from 10 to 950, from 10 to 900, from 10 to 850, from 10 to 800, from 10 to 750, from 10 to 700, from 10 to 650, from 10 to 600, from 10 to 550, from 10 to 500, from 10 to 450, from 10 to 400, from 10 to 350, from 10 to 300, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 90, from 10 to 80, from 10 to 70, from 10 to 60, from 10 to 50, from 10 to 40, from 10 to 30, or from 10 to 20. In some embodiments, the molecular weight of the hydrophobic moiety is from 10 to 3,500, from 50 to 3,000, from 100 to 2,500, from 150 to 2,000, from 200 to 1,500, from 250 to 1,000, from 300 to 950, from 350 to 900, from 400 to 850, from 450 to 800, from 500 to 750, from 550 to 700, or from 600 to 650.

[0348] In some embodiments, X and Y are independently a non-cleavable bond or a cleavable bond. In some embodiments, the non-cleavable bond is an amide bond or a phosphorylated bond. In some embodiments, the cleavable bond is any one selected from the group consisting of a disulfide bond, an acid-cleavable bond, an ester bond, an anhydride bond, a biodegradable bond, and an enzyme-cleavable bond.

[0349] In another aspect, nanoparticles comprising the compounds provided herein are provided herein. In another aspect, compositions comprising the compounds provided herein or the nanoparticles provided herein are provided herein. In another aspect, pharmaceutical compositions comprising the compounds provided herein, the nanoparticles provided herein, or the compositions provided herein, and a pharmaceutically acceptable excipient, carrier, or diluent are provided herein.

[0350] Target molecule In some embodiments, the target molecule is any one selected from the group consisting of BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, α-synuclein, huntingtin (Htt), Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, and RhoA.

[0351] In some embodiments, the target molecule is BACE1-AS, and the compounds provided herein regulate the expression and / or activity of BACE1-AS by targeting the mRNA transcribed from the BACE1-AS genomic sequence (exemplary sequence: ENSG 00000278768). In some embodiments, the target molecule is BACE1-AS, and the compounds provided herein reduce or inhibit the expression and / or activity of BACE1-AS by targeting the mRNA transcribed from the BACE1-AS genomic sequence (exemplary sequence: ENSG 00000278768). In some embodiments, the compounds provided herein may target any region of the BACE1-AS mRNA.

[0352] In some embodiments, the target molecule is beta-secretase 1 (BACE1), and the compounds provided herein regulate the expression and / or activity of BACE1 (UniProt number for BACE1 protein: P56817) by targeting the mRNA transcribed from the BACE1 genomic sequence (exemplary sequence: ENSG00000186318). In some embodiments, the target molecule is beta-secretase 1 (BACE1), and the compounds provided herein reduce or inhibit the expression and / or activity of BACE1 (UniProt number for BACE1 protein: P56817) by targeting the mRNA transcribed from the BACE1 genomic sequence (exemplary sequence: ENSG00000186318). In some embodiments, the compounds provided herein may target any region of BACE1 mRNA.

[0353] In some embodiments, the target molecule is presenilin 1 (PS1), and the compounds provided herein regulate the expression and / or activity of presenilin 1 (PS1) (UniProt number for presenilin 1 (PS1) protein: P49768) by targeting the mRNA transcribed from the presenilin 1 (PS1) genomic sequence (exemplary sequence: ENSG00000080815). In some embodiments, the target molecule is presenilin 1 (PS1), and the compounds provided herein reduce or inhibit the expression and / or activity of presenilin 1 (PS1) (UniProt number for presenilin 1 (PS1) protein: P49768) by targeting the mRNA transcribed from the presenilin 1 (PS1) genomic sequence (exemplary sequence: ENSG00000080815). In some embodiments, the compounds provided herein may target any region of presenilin 1 (PS1) mRNA.

[0354] In some embodiments, the target molecule is Rho - associated protein kinase II (ROCK - II), and the compounds provided herein regulate the expression and / or activity of ROCK - II (UniProt number for ROCK - II protein: O75116) by targeting the mRNA transcribed from the ROCK - II genomic sequence (exemplary sequence: ENSG00000134318). In some embodiments, the target molecule is Rho - associated protein kinase II (ROCK - II), and the compounds provided herein reduce or inhibit the expression and / or activity of ROCK - II (UniProt number O75116 for ROCK - II protein) by targeting the mRNA transcribed from the ROCK - II genomic sequence (exemplary sequence: ENSG00000134318). In some embodiments, the compounds provided herein can target any region of the ROCK - II mRNA.

[0355] In some embodiments, the target molecule is I2PP - 2A (protein SET), and the compounds provided herein regulate the expression and / or activity of I2PP - 2A (UniProt number for I2PP - 2A protein: Q01105) by targeting the mRNA transcribed from the I2PP - 2A genomic sequence (exemplary sequence: ENSG00000119335). In some embodiments, the target molecule is I2PP - 2A (protein SET), and the compounds provided herein reduce or inhibit the expression and / or activity of I2PP - 2A (UniProt number Q01105 for I2PP - 2A protein) by targeting the mRNA transcribed from the I2PP - 2A genomic sequence (exemplary sequence: ENSG00000119335). In some embodiments, the compounds provided herein can target any region of the I2PP - 2A mRNA.

[0356] In some embodiments, the target molecule is acetyl-CoA acetyltransferase, mitochondrial (ACAT-1), and the compounds provided herein regulate the expression and / or activity of ACAT-1 (UniProt number for ACAT-1: P24752) by targeting the mRNA transcribed from the ACAT-1 genomic sequence (exemplary sequence: ENSG00000075239). In some embodiments, the target molecule is acetyl-CoA acetyltransferase, mitochondrial (ACAT-1), and the compounds provided herein reduce or inhibit the expression and / or activity of ACAT-1 (UniProt number for ACAT-1: P24752) by targeting the mRNA transcribed from the ACAT-1 genomic sequence (exemplary sequence: ENSG00000075239). In some embodiments, the compounds provided herein can target any region of the ACAT-1 mRNA.

[0357] In some embodiments, the target molecule is the Nogo receptor (Reticulon 4 receptor (RTN4R)), and the compounds provided herein regulate the expression and / or activity of the Nogo receptor (UniProt number for the Nogo receptor protein: Q9BZR6) by targeting the mRNA transcribed from the Nogo receptor genomic sequence (exemplary sequence: ENSG00000040608). In some embodiments, the target molecule is the Nogo receptor (Reticulon 4 receptor (RTN4R)), and the compounds provided herein reduce or inhibit the expression and / or activity of the Nogo receptor (UniProt number for the Nogo receptor protein: Q9BZR6) by targeting the mRNA transcribed from the Nogo receptor genomic sequence (exemplary sequence: ENSG00000040608). In some embodiments, the compounds provided herein can target any region of the Nogo receptor mRNA.

[0358] In some embodiments, the target molecule is mutant presenilin 1 (L392V PS-1), i.e., presenilin 1 containing the L392V mutation, and the compounds provided herein modulate the expression and / or activity of mutant presenilin 1 (L392V PS-1) by targeting the mRNA transcribed from the presenilin 1 genomic sequence containing the L392V mutation. In some embodiments, the target molecule is mutant presenilin 1 (L392V PS-1), i.e., presenilin 1 containing the L392V mutation, and the compounds provided herein reduce or inhibit the expression and / or activity of mutant presenilin 1 (L392V PS-1) by targeting the mRNA transcribed from the presenilin 1 genomic sequence containing the L392V mutation. In some embodiments, the compounds provided herein can target any region of the mutant presenilin 1 (L392V PS-1) mRNA.

[0359] In some embodiments, the target molecule is APP (amyloid-beta precursor protein), and the compounds as provided herein modulate the expression and / or activity of APP (UniProt number for APP protein: P05067) by targeting the mRNA transcribed from the APP genomic sequence (exemplary sequence: ENSG00000142192). In some embodiments, the target molecule is APP (amyloid-beta precursor protein), and the compounds as provided herein reduce or inhibit the expression and / or activity of APP (UniProt number for APP protein: P05067) by targeting the mRNA transcribed from the APP genomic sequence (exemplary sequence: ENSG00000142192). In some embodiments, the compounds provided herein can target any region of the APP mRNA.

[0360] In some embodiments, the target molecule is Tau (tubulin binding unit), and the compounds provided herein modulate the expression and / or activity of Tau (UniProt number for Tau protein: P10636) by targeting the mRNA transcribed from the Tau genomic sequence (exemplary sequences: ENSG00000186868; ENSG00000276155; or ENSG00000277956). In some embodiments, the target molecule is Tau (tubulin binding unit), and the compounds provided herein reduce or inhibit the expression and / or activity of Tau (UniProt number for Tau protein: P10636) by targeting the mRNA transcribed from the Tau genomic sequence (exemplary sequences: ENSG00000186868; ENSG00000276155; or ENSG00000277956). In some embodiments, the compounds provided herein may target any region of Tau mRNA.

[0361] In some embodiments, the target molecule is voltage-dependent anion-selective channel 1 (VDAC1), and the compounds provided herein modulate the expression and / or activity of VDAC1 (UniProt number for VDAC1 protein: P21796) by targeting the mRNA transcribed from the VDAC1 genomic sequence (exemplary sequence: ENSG00000213585). In some embodiments, the target molecule is voltage-dependent anion-selective channel 1 (VDAC1), and the compounds provided herein reduce or inhibit the expression and / or activity of VDAC1 (UniProt number for VDAC1 protein: P21796) by targeting the mRNA transcribed from the VDAC1 genomic sequence (exemplary sequence: ENSG00000213585). In some embodiments, the compounds provided herein may target any region of VDAC1 mRNA.

[0362] In some embodiments, the target molecule is α-synuclein, and the compounds provided herein regulate the expression and / or activity of α-synuclein (UniProt number for α-synuclein protein: P37840) by targeting the mRNA transcribed from the α-synuclein genomic sequence (exemplary sequence: ENSG00000145335). In some embodiments, the target molecule is α-synuclein, and the compounds provided herein reduce or inhibit the expression and / or activity of α-synuclein (UniProt number for α-synuclein protein: P37840) by targeting the mRNA transcribed from the α-synuclein genomic sequence (exemplary sequence: ENSG00000145335). In some embodiments, the compounds provided herein can target any region of the α-synuclein mRNA.

[0363] In some embodiments, the target molecule is huntingtin (Htt), and the compounds provided herein regulate the expression and / or activity of Htt (UniProt number for Htt protein: P42858) by targeting the mRNA transcribed from the Htt genomic sequence (exemplary sequence: ENSG00000197386). In some embodiments, the target molecule is huntingtin (Htt), and the compounds provided herein reduce or inhibit the expression and / or activity of Htt (UniProt number for Htt protein: P42858) by targeting the mRNA transcribed from the Htt genomic sequence (exemplary sequence: ENSG00000197386). In some embodiments, the compounds provided herein can target any region of the Htt mRNA.

[0364] In some embodiments, the target molecule is the neurogenic locus notch homolog protein 1 (Notch1), and the compounds provided herein target the mRNA transcribed from the Notch1 genomic sequence (exemplary sequence: ENSG00000148400) to regulate the expression and / or activity of Notch1 (UniProt number for Notch1 protein: P46531). In some embodiments, the target molecule is the neurogenic locus notch homolog protein 1 (Notch1), and the compounds provided herein target the mRNA transcribed from the Notch1 genomic sequence (exemplary sequence: ENSG00000148400) to reduce or inhibit the expression and / or activity of Notch1 (UniProt number for Notch1 protein: P46531). In some embodiments, the compounds provided herein can target any region of Notch1 mRNA.

[0365] In some embodiments, the target molecule is leucine rich repeat and immunoglobulin like domain containing protein 1 (LINGO-1), and the compounds provided herein target the mRNA transcribed from the LINGO-1 genomic sequence (exemplary sequence: ENSG00000169783) to regulate the expression and / or activity of LINGO-1 (UniProt number for LINGO-1 protein: Q96FE5). In some embodiments, the target molecule is leucine rich repeat and immunoglobulin like domain containing protein 1 (LINGO-1), and the compounds provided herein target the mRNA transcribed from the LINGO-1 genomic sequence (exemplary sequence: ENSG00000169783) to reduce or inhibit the expression and / or activity of LINGO-1 (UniProt number for LINGO-1 protein: Q96FE5). In some embodiments, the compounds provided herein can target any region of LINGO-1 mRNA.

[0366] In some embodiments, the target molecule is nuclear receptor 4A2 (NR4A2), and the compounds provided herein regulate the expression and / or activity of NR4A2 (UniProt number for NR4A2 protein: P43354) by targeting the mRNA transcribed from the NR4A2 genomic sequence (exemplary sequence: ENSG 00000153234). In some embodiments, the target molecule is nuclear receptor 4A2 (NR4A2), and the compounds provided herein reduce or inhibit the expression and / or activity of NR4A2 (UniProt number for NR4A2 protein: P43354) by targeting the mRNA transcribed from the NR4A2 genomic sequence (exemplary sequence: ENSG 00000153234). In some embodiments, the compounds provided herein can target any region of NR4A2 mRNA.

[0367] In some embodiments, the target molecule is Toll / Interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF), and the compounds provided herein regulate the expression and / or activity of TRIF (UniProt number for TRIF protein: Q8IUC6) by targeting the mRNA transcribed from the TRIF genomic sequence (exemplary sequence: ENSG00000127666). In some embodiments, the target molecule is Toll / Interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF), and the compounds provided herein reduce or inhibit the expression and / or activity of TRIF (UniProt number for TRIF protein: Q8IUC6) by targeting the mRNA transcribed from the TRIF genomic sequence (exemplary sequence: ENSG00000127666). In some embodiments, the compounds provided herein can target any region of TRIF mRNA.

[0368] In some embodiments, the target molecule is caspase-2, and the compounds provided herein modulate the expression and / or activity of caspase-2 (UniProt number for caspase-2 protein: P42575) by targeting mRNA transcribed from the caspase-2 genomic sequence (exemplary sequence: ENSG00000106144). In some embodiments, the target molecule is caspase-2, and the compounds provided herein reduce or inhibit the expression and / or activity of caspase-2 (UniProt number for caspase-2 protein: P42575) by targeting mRNA transcribed from the caspase-2 genomic sequence (exemplary sequence: ENSG00000106144). In some embodiments, the compounds provided herein may target any region of caspase-2 mRNA.

[0369] In some embodiments, the target molecule is Ca2+ / calmodulin-dependent protein kinase II (CaMKII), such as Ca2+ / calmodulin-dependent protein kinase II alpha (CaMKII alpha) and / or Ca2+ / calmodulin-dependent protein kinase II beta (CaMKII beta), and the compounds provided herein regulate the expression and / or activity of CaMKII alpha (UniProt number: Q9UQM7 for the CaMKII alpha protein) and / or CaMKII beta (UniProt number: Q13554 for the CaMKII beta protein) by targeting the mRNA transcribed from the CaMKII alpha genomic sequence (exemplary sequence: ENSG00000058404) or the CaMKII beta genomic sequence (exemplary sequence: ENSG00000106144). In some embodiments, the target molecule is Ca2+ / calmodulin-dependent protein kinase II (CaMKII), such as Ca2+ / calmodulin-dependent protein kinase II alpha (CaMKII alpha) and / or Ca2+ / calmodulin-dependent protein kinase II beta (CaMKII beta), and the compounds provided herein reduce or inhibit the expression and / or activity of CaMKII alpha (UniProt number: Q9UQM7 for the CaMKII alpha protein) and / or CaMKII beta (UniProt number: Q13554 for the CaMKII beta protein) by targeting the mRNA transcribed from the CaMKII alpha genomic sequence (exemplary sequence: ENSG00000058404) or the CaMKII beta genomic sequence (exemplary sequence: ENSG00000106144). In some embodiments, the compounds provided herein may target any region of CaMKII alpha mRNA or CaMKII beta mRNA.

[0370] In some embodiments, the target molecule is glial fibrillary acidic protein (GFAP), and the provided compound regulates the expression and / or activity of GFAP (UniProt number for GFAP protein: P14136) by targeting the mRNA transcribed from the GFAP genomic sequence (exemplary sequence: ENSG00000131095). In some embodiments, the target molecule is glial fibrillary acidic protein (GFAP), and the provided compound reduces or inhibits the expression and / or activity of GFAP (UniProt number for GFAP protein: P14136) by targeting the mRNA transcribed from the GFAP genomic sequence (exemplary sequence: ENSG00000131095). In some embodiments, the compounds provided herein may target any region of GFAP mRNA.

[0371] In some embodiments, the target molecule is vimentin, and the compounds provided herein regulate the expression and / or activity of vimentin (UniProt number for vimentin protein: P08670) by targeting the mRNA transcribed from the vimentin genomic sequence (exemplary sequence: ENSG 00000026025). In some embodiments, the target molecule is vimentin, and the compounds provided herein reduce or inhibit the expression and / or activity of vimentin (UniProt number for vimentin protein: P08670) by targeting the mRNA transcribed from the vimentin genomic sequence (exemplary sequence: ENSG 00000026025). In some embodiments, the compounds provided herein may target any region of vimentin mRNA.

[0372] In some embodiments, the target molecule is Ephrin B type receptor 3 (EphB3), and the compounds provided herein regulate the expression and / or activity of EphB3 (UniProt number for EphB3 protein: P54753) by targeting mRNA transcribed from the EphB3 genomic sequence (exemplary sequence: ENSG00000182580). In some embodiments, the target molecule is Ephrin B type receptor 3 (EphB3), and the compounds provided herein reduce or inhibit the expression and / or activity of EphB3 (UniProt number for EphB3 protein: P54753) by targeting mRNA transcribed from the EphB3 genomic sequence (exemplary sequence: ENSG00000182580). In some embodiments, the compounds provided herein can target any region of EphB3 mRNA.

[0373] In some embodiments, the target molecule is inducible nitric oxide synthase (iNOS), and the compounds provided herein regulate the expression and / or activity of iNOS (UniProt number for iNOS protein: P35228) by targeting mRNA transcribed from the iNOS genomic sequence (exemplary sequence: ENSG00000007171). In some embodiments, the target molecule is inducible nitric oxide synthase (iNOS), and the compounds provided herein reduce or inhibit the expression and / or activity of iNOS (UniProt number for iNOS protein: P35228) by targeting mRNA transcribed from the iNOS genomic sequence (exemplary sequence: ENSG00000007171). In some embodiments, compounds as provided herein can target any region of iNOS mRNA.

[0374] In some embodiments, the target molecule is nischarin, and the compounds provided herein regulate the expression and / or activity of nischarin (UniProt number for Nischarin protein: Q9Y2I1) by targeting the mRNA transcribed from the genomic sequence of nischarin (exemplary sequence: ENSG00000010322). In some embodiments, the target molecule is nischarin, and the compounds provided herein reduce or inhibit the expression and / or activity of nischarin (UniProt number for Nischarin protein: Q9Y2I1) by targeting the mRNA transcribed from the genomic sequence of nischarin (exemplary sequence: ENSG00000010322). In some embodiments, the compounds provided herein can target any region of Nischarin mRNA.

[0375] In some embodiments, the target molecule is transforming protein RhoA (RhoA), and the compounds provided herein regulate the expression and / or activity of RhoA (UniProt number for RhoA protein: P61586) by targeting the mRNA transcribed from the RhoA genomic sequence (exemplary sequence: ENSG00000067560). In some embodiments, the target molecule is transforming protein RhoA (RhoA), and the compounds provided herein reduce or inhibit the expression and / or activity of RhoA (UniProt number for RhoA protein: P61586) by targeting the mRNA transcribed from the RhoA genomic sequence (exemplary sequence: ENSG00000067560). In some embodiments, the compounds provided herein can target any region of RhoA mRNA.

[0376] In some embodiments, the target molecule is any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E. In some embodiments, the compounds provided herein modulate the expression and / or activity of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E. In some embodiments, the compounds provided herein reduce or inhibit the expression and / or activity of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E. In some embodiments, the compounds provided herein modulate the expression and / or activity of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E by targeting mRNA transcribed from the genomic sequence of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E. In some embodiments, the compounds provided herein reduce or inhibit the expression and / or activity of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E by targeting mRNA transcribed from the genomic sequence of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E. In some embodiments, the compounds provided herein may target any region of the mRNA of any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, and Table 6E.

[0377] In some embodiments, R modulates the expression and / or activity of the target molecule. In some embodiments, R modulates the expression of the target molecule. In some embodiments, R modulates the activity of the target molecule.

[0378] In some embodiments, R modulates the expression of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% compared to the expression of the target molecule in a subject tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, R modulates the activity of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% compared to the expression of the target molecule in a subject tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, the expression of the target molecule is modulated by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or about 100% by a compound provided herein compared to the expression of the target molecule in a control tissue, organ, cell or subject not treated with a compound provided herein. In some embodiments, the activity of the target molecule is modulated by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or about 100% by a compound provided herein compared to the activity of the target molecule in a control tissue, organ, cell or subject not treated with a compound provided herein.

[0379] In some embodiments, R reduces and / or inhibits the expression and / or activity of the target molecule. In some embodiments, R reduces or inhibits the expression of the target molecule. In some embodiments, R reduces or inhibits the activity of the target molecule.

[0380] In some embodiments, R reduces or inhibits the expression of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% as compared to the expression of the target molecule in a target tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, R reduces or inhibits the activity of the target molecule by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or 100% as compared to the expression of the target molecule in a target tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, the expression of the target molecule is reduced or inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or about 100% by a compound as provided herein as compared to the expression of the target molecule in a control tissue, organ, cell or subject not treated with a compound as provided herein. In some embodiments, the activity of the target molecule is reduced or inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9% or about 100% by a compound as provided herein as compared to the activity of the target molecule in a control tissue, organ, cell or subject not treated with a compound as provided herein.

[0381] In some embodiments, the double-stranded oligonucleotide construct comprises a sense and antisense pair targeting hu-BACE1 selected from: #081, #001, #091, #131, #135, #177, #175, #093, #056, #009, #002, and #072, or combinations thereof (or pairs selected from Tables 2C, 2D, 2E, 2F, and 2G). In some embodiments, the double-stranded oligonucleotide construct is selected from: AGGCACCACCCCTTGGAAC (SEQ ID NO: 22) and GUUCCAAGGGGUGGUGCCU (SEQ ID NO: 23), CCAGCACATACCGGGACCT (SEQ ID NO: 24) and AGGUCCCGGUAUGUGCUGG (SEQ ID NO: 25), GGTGAGGTTACCAACCAGT (SEQ ID NO: 26) and ACUGGUUGGUAACCUCACC (SEQ ID NO: 27), CCCGAAAACGAATTGGCTT (SEQ ID NO: 28) and AAGCCAAUUCGUUUUCGGG (SEQ ID NO: 29), TGGCTTTGCTGTCAGCGCT (SEQ ID NO: 30) and AGCGCUGACAGCAAAGCCA (SEQ ID NO: 31), TACTCTTGGTCACCTCAAA (SEQ ID NO: 32) and UUUGAGGUGACCAAGAGUA (SEQ ID NO: 33), AATACTCTTGGTCACCTCA (SEQ ID NO: 34) and UGAGGUGACCAAGAGUAUU (SEQ ID NO: 35), CCAACCAGTCCTTCCGCAT (SEQ ID NO: 36) and AUGCGGAAGGACUGGUUGG (SEQ ID NO: 37), ATCCGGCGGGAGTGGTATT (SEQ ID NO: 38) and AAUACCACUCCCGCCGGAU (SEQ ID NO: 39), CCTCCGGAAGGGTGTGTAT (SEQ ID NO: 40) and CAGCACATACCGGGACCTC (SEQ ID NO: 42); or GGGTGGAGATCAATGGACA (SEQ ID NO: 44) and UGUCCAUUGAUCUCCACCC (SEQ ID NO: 45), or combinations thereof.

[0382] In some embodiments, the oligonucleotide comprises a sense strand having at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), CCAGCACATACCGGGACCT (SEQ ID NO: 24), GGTGAGGTTACCAACCAGT (SEQ ID NO: 26), CCCGAAAACGAATTGGCTT (SEQ ID NO: 28), TGGCTTTGCTGTCAGCGCT (SEQ ID NO: 30), TACTCTTGGTCACCTCAAA (SEQ ID NO: 32), AATACTCTTGGTCACCTCA (SEQ ID NO: 34), CCAACCAGTCCTTCCGCAT (SEQ ID NO: 36), ATCCGGCGGGAGTGGTATT (SEQ ID NO: 38), CCTCCGGAAGGGTGTGTAT (SEQ ID NO: 40), CAGCACATACCGGGACCTC (SEQ ID NO: 42), or GGGTGGAGATCAATGGACA (SEQ ID NO: 44), or combinations thereof. In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), CCAGCACATACCGGGACCT (SEQ ID NO: 24), GGTGAGGTTACCAACCAGT (SEQ ID NO: 26), and TACTCTTGGTCACCTCAAA (SEQ ID NO: 32), or combinations thereof.

[0383] In some embodiments, the double-stranded oligonucleotide construct comprises a sense pair and an antisense pair targeting hu-MAPT selected from #059, #326, #024, #310, #319, #102, #103, #327, #286, #118, #111 and #091, or combinations thereof (or pairs selected from Table 2C, Table 2D, Table 2E, Table 2F and Table 2G). In some embodiments, the double-stranded oligonucleotide construct comprises a sense pair and an antisense pair selected from GGGCTGATGGTAAAACGAA (SEQ ID NO: 46) and UUCGUUUUACCAUCAGCCC (SEQ ID NO: 47), CTGGTCTGGCTTGCGGCGC (SEQ ID NO: 48) and GCGCCGCAAGCCAGACCAG (SEQ ID NO: 49), GGAAGATCACGCTGGGACG (SEQ ID NO: 50) and CGUCCCAGCGUGAUCUUCC (SEQ ID NO: 51), AGCTAAGGAGGCCGTTCAG (SEQ ID NO: 52) and CUGAACGGCCUCCUUAGCU (SEQ ID NO: 53), GGATTAGGACTGAAGCGAT (SEQ ID NO: 54) and AUCGCUUCAGUCCUAAUCC (SEQ ID NO: 55), CCGTACTCCACCCAAGTCG (SEQ ID NO: 56) and CGACUUGGGUGGAGUACGG (SEQ ID NO: 57), CGTACTCCACCCAAGTCGC (SEQ ID NO: 58) and GCGACUUGGGUGGAGUACG (SEQ ID NO: 59), CTGGCTTGCGGCGCGAGGA (SEQ ID NO: 60) and UCCUCGCGCCGCAAGCCAG (SEQ ID NO: 61), TTCTAACCCACCCTCACGA (SEQ ID NO: 62) and UCGUGAGGGUGGGUUAGAA (SEQ ID NO: 63), AAGTCCAAGATCGGCTCCA (SEQ ID NO: 64) and UGGAGCCGAUCUUGGACUU (SEQ ID NO: 65), TCGCCGTCTTCCGCCAAGA (SEQ ID NO: 66) and UCUUGGCGGAAGACGGCGA (SEQ ID NO: 67), or GGATCGCAGCGGCTACAGC (SEQ ID NO: 68) and GCUGUAGCCGCUGCGAUCC (SEQ ID NO: 69), or combinations thereof.

[0384] In some embodiments, the oligonucleotide comprises a sense strand having at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from GGGCTGATGGTAAAACGAA (SEQ ID NO: 46), CTGGTCTGGCTTGCGGCGC (SEQ ID NO: 48), GGAAGATCACGCTGGGACG (SEQ ID NO: 50), AGCTAAGGAGGCCGTTCAG (SEQ ID NO: 52), GGATTAGGACTGAAGCGAT (SEQ ID NO: 54), CCGTACTCCACCCAAGTCG (SEQ ID NO: 56), CGTACTCCACCCAAGTCGC (SEQ ID NO: 58), CTGGCTTGCGGCGCGAGGA (SEQ ID NO: 60), TTCTAACCCACCCTCACGA (SEQ ID NO: 62), AAGTCCAAGATCGGCTCCA (SEQ ID NO: 64), TCGCCGTCTTCCGCCAAGA (SEQ ID NO: 66), or GGATCGCAGCGGCTACAGC (SEQ ID NO: 68) or combinations thereof. In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from GGGCTGATGGTAAAACGAA (SEQ ID NO: 46), CTGGTCTGGCTTGCGGCGC (SEQ ID NO: 48), GGAAGATCACGCTGGGACG (SEQ ID NO: 50), AGCTAAGGAGGCCGTTCAG (SEQ ID NO: 52), and CCGTACTCCACCCAAGTCG (SEQ ID NO: 56) or combinations thereof.

[0385] In some embodiments, the nanoparticles are formed of two or more compounds, the two or more compounds include two or more oligonucleotides, and one of the oligonucleotides includes a sense pair and an antisense pair selected from #081, #001, #091, #131, #135, #177, #175, #093, #056, #009, #002, and #072, or combinations thereof (or pairs selected from Table 2C, Table 2D, Table 2E, Table 2F, and Table 2G), and one of the oligonucleotides includes #059, #326, #024, #310, #319, #102, #103, #327, #286, #118, #111, and #091, or combinations thereof (or pairs selected from Table 2C, Table 2D, Table 2E, Table 2F, and Table 2G), or combinations thereof.

[0386] In some embodiments, the nanoparticles are formed of two or more compounds, the two or more compounds include two or more oligonucleotides, and one of the oligonucleotides is AGGCACCACCCCTTGGAAC (SEQ ID NO: 22) and GUUCCAAGGGGUGGUGCCU (SEQ ID NO: 23), CCAGCACATACCGGGACCT (SEQ ID NO: 24) and AGGUCCCGGUAUGUGCUGG (SEQ ID NO: 25), GGTGAGGTTACCAACCAGT (SEQ ID NO: 26) and ACUGGUUGGUAACCUCACC (SEQ ID NO: 27), CCCGAAAACGAATTGGCTT (SEQ ID NO: 28) and AAGCCAAUUCGUUUUCGGG (SEQ ID NO: 29), TGGCTTTGCTGTCAGCGCT (SEQ ID NO: 30) and AGCGCUGACAGCAAAGCCA (SEQ ID NO: 31), TACTCTTGGTCACCTCAAA (SEQ ID NO: 32) and UUUGAGGUGACCAAGAGUA (SEQ ID NO: 33), AATACTCTTGGTCACCTCA (SEQ ID NO: 34) and UGAGGUGACCAAGAGUAUU (SEQ ID NO: 35), CCAACCAGTCCTTCCGCAT (SEQ ID NO: 36) and AUGCGGAAGGACUGGUUGG (SEQ ID NO: 37), ATCCGGCGGGAGTGGTATT (SEQ ID NO: 38) and AAUACCACUCCCGCCGGAU (SEQ ID NO: 39), CCTCCGGAAGGGTGTGTAT (SEQ ID NO: 40) and CAGCACATACCGGGACCTC (SEQ ID NO: 42);comprising a sense pair and an antisense pair selected from either GGGTGGAGATCAATGGACA (SEQ ID NO: 44) and UGUCCAUUGAUCUCCACCC (SEQ ID NO: 45), or a combination thereof, wherein one of the oligonucleotides is selected from GGGCTGATGGTAAAACGAA (SEQ ID NO: 46) and UUCGUUUUACCAUCAGCCC (SEQ ID NO: 47), CTGGTCTGGCTTGCGGCGC (SEQ ID NO: 48) and GCGCCGCAAGCCAGACCAG (SEQ ID NO: 49), GGAAGATCACGCTGGGACG (SEQ ID NO: 50) and CGUCCCAGCGUGAUCUUCC (SEQ ID NO: 51), AGCTAAGGAGGCCGTTCAG (SEQ ID NO: 52) and CUGAACGGCCUCCUUAGCU (SEQ ID NO: 53), GGATTAGGACTGAAGCGAT (SEQ ID NO: 54) and AUCGCUUCAGUCCUAAUCC (SEQ ID NO: 55), CCGTACTCCACCCAAGTCG (SEQ ID NO: 56) and CGACUUGGGUGGAGUACGG (SEQ ID NO: 57), CGTACTCCACCCAAGTCGC (SEQ ID NO: 58) and GCGACUUGGGUGGAGUACG (SEQ ID NO: 59), CTGGCTTGCGGCGCGAGGA (SEQ ID NO: 60) and UCCUCGCGCCGCAAGCCAG (SEQ ID NO: 61), TTCTAACCCACCCTCACGA (SEQ ID NO: 62) and UCGUGAGGGUGGGUUAGAA (SEQ ID NO: 63), AAGTCCAAGATCGGCTCCA (SEQ ID NO: 64) and UGGAGCCGAUCUUGGACUU (SEQ ID NO: 65), TCGCCGTCTTCCGCCAAGA (SEQ ID NO: 66) and UCUUGGCGGAAGACGGCGA (SEQ ID NO: 67), or GGATCGCAGCGGCTACAGC (SEQ ID NO: 68) and GCUGUAGCCGCUGCGAUCC (SEQ ID NO: 69), or a combination thereof.;

[0387] In some embodiments, the nanoparticles are formed of two or more compounds, the two or more compounds include two or more oligonucleotides, and one of the oligonucleotides has a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), CCAGCACATACCGGGACCT (SEQ ID NO: 24), GGTGAGGTTACCAACCAGT (SEQ ID NO: 26), CCCGAAAACGAATTGGCTT (SEQ ID NO: 28), TGGCTTTGCTGTCAGCGCT (SEQ ID NO: 30), TACTCTTGGTCACCTCAAA (SEQ ID NO: 32), AATACTCTTGGTCACCTCA (SEQ ID NO: 34), CCAACCAGTCCTTCCGCAT (SEQ ID NO: 36), ATCCGGCGGGAGTGGTATT (SEQ ID NO: 38), CCTCCGGAAGGGTGTGTAT (SEQ ID NO: 40), CAGCACATACCGGGACCTC (SEQ ID NO: 42), and GGGTGGAGATCAATGGACA (SEQ ID NO: 44) or combinations thereof, and one of the oligonucleotides includes a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from GGGCTGATGGTAAAACGAA (SEQ ID NO: 46), CTGGTCTGGCTTGCGGCGC (SEQ ID NO: 48), GGAAGATCACGCTGGGACG (SEQ ID NO: 50), AGCTAAGGAGGCCGTTCAG (SEQ ID NO: 52), GGATTAGGACTGAAGCGAT (SEQ ID NO: 54), CCGTACTCCACCCAAGTCG (SEQ ID NO: 56), CGTACTCCACCCAAGTCGC (SEQ ID NO: 58), CTGGCTTGCGGCGCGAGGA (SEQ ID NO: 60), TTCTAACCCACCCTCACGA (SEQ ID NO: 62), AAGTCCAAGATCGGCTCCA (SEQ ID NO: 64), TCGCCGTCTTCCGCCAAGA (SEQ ID NO: 66), or GGATCGCAGCGGCTACAGC (SEQ ID NO: 68) or combinations thereof.

[0388] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide has a sense strand (the sense strand of hu-BACE1 pair #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), and an antisense strand (the antisense strand of hu-BACE1 pair #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GUUCCAAGGGGUGGUGCCU (SEQ ID NO: 23).

[0389] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide has a sense strand (the sense strand of hu-BACE1 pair #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCUUGGAAC (SEQ ID NO: 136), and an antisense strand (the antisense strand of hu-BACE1 pair #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GUUCCAAGGGGUGGUGCCU (SEQ ID NO: 23).

[0390] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide has a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCTTGGAAC (SEQ ID NO: 22) (the sense strand of hu-BACE1 pair #81) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GTTCCAAGGGGTGGTGCCT (SEQ ID NO: 137) (the antisense strand of hu-BACE1 pair #81).

[0391] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide has a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCUUGGAAC (SEQ ID NO: 136) (the sense strand of hu-BACE1 pair #81) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GTTCCAAGGGGTGGTGCCT (SEQ ID NO: 137) (the antisense strand of hu-BACE1 pair #81).

[0392] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide has a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGATCACGCTGGGACG (SEQ ID NO: 50) (the sense strand of hu-MAPT pair #24) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to CGUCCCAGCGUGAUCUUCC (SEQ ID NO: 51) (the antisense strand of hu-MAPT pair #24).

[0393] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide has a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGAUCACGCUGGGACG (SEQ ID NO: 164) (the sense strand of hu-MAPT pair #24) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to CGTCCCAGCGTGATCTTCC (SEQ ID NO: 165) (the antisense strand of hu-MAPT pair #24).

[0394] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide includes a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGAUCACGCUGGGACG (SEQ ID NO: 164) (the sense strand of hu-MAPT pair #24) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to CGUCCCAGCGUGAUCUUCC (SEQ ID NO: 51) (the antisense strand of hu-MAPT pair #24).

[0395] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, and the first oligonucleotide includes a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGATCACGCTGGGACG (SEQ ID NO: 50) (the sense strand of hu-MAPT pair #24) and an antisense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to CGTCCCAGCGTGATCTTCC (SEQ ID NO: 165) (the antisense strand of hu-MAPT pair #24).

[0396] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide includes a sense strand (the sense strand of BACE1 vs. #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), and the second oligonucleotide includes an antisense strand (the sense strand of MAPT#24) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGATCACGCTGGGACG (SEQ ID NO: 50).

[0397] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide includes a sense strand (the sense strand of BACE1 vs. #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCUUGGAAC (SEQ ID NO: 136), and the second oligonucleotide includes an antisense strand (the sense strand of MAPT#24) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGATCACGCTGGGACG (SEQ ID NO: 50).

[0398] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide includes a sense strand (the sense strand of BACE1 vs. #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCUUGGAAC (SEQ ID NO: 136), and the second oligonucleotide includes an antisense strand (the sense strand of MAPT#24) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGAUCACGCUGGGACG (SEQ ID NO: 164).

[0399] In some embodiments, the nanoparticles are formed of one or more compounds, the one or more compounds include one or more double-stranded oligonucleotides, the first oligonucleotide includes a sense strand (the sense strand of BACE1 vs. #81) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to AGGCACCACCCCTTGGAAC (SEQ ID NO: 22), and the second oligonucleotide includes an antisense strand (the sense strand of MAPT#24) having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to GGAAGAUCACGCUGGGACG (SEQ ID NO: 164).

[0400] In some embodiments, the double-stranded oligonucleotide construct comprises a sense and antisense pair selected from: #035, #024, #032, #034, #006, #003, #028, #030, #029, #022, #023, #002, #004, #017, #015, #033, #027, #026, and #025, or combinations thereof (or pairs selected from Table 2C, Table 2D, Table 2E, Table 2F, and Table 2G). In some embodiments, two or more compounds form a particle and they comprise two or more oligonucleotides, one of the oligonucleotides being AACGTCACTGTGCGTGCCA (SEQ ID NO:70) and UGGCACGCACAGUGACGUU (SEQ ID NO:71), CGGGAGACCGACGAGGAAT (SEQ ID NO:72) and AUUCCUCGUCGGUCUCCCG (SEQ ID NO:73), GGAGGAGCCTGGCCGGAGA (SEQ ID NO:74) and UCUCCGGCCAGGCUCCUCC (SEQ ID NO:75), TCCGGCTGCCCCTTCGCAG (SEQ ID NO:76) and CUGCGAAGGGGCAGCCGGA (SEQ ID NO:77), GGAGCCCGGAGTCCCTGTC (SEQ ID NO:78) and GACAGGGACUCCGGGCUCC (SEQ ID NO:79), TGCCTAGGTGCTGGGAGCT (SEQ ID NO:80) and AGCUCCCAGCACCUAGGCA)(SEQ ID NO:81), CGGGCAGTAGTAACTTTGC (SEQ ID NO:82) and GCAAAGUUACUACUGCCCG (SEQ ID NO:83), GCTGTCCAGCACATATCGA (SEQ ID NO:84) and UCGAUAUGUGCUGGACAGC (SEQ ID NO:85), ACCCTTTCCTGCATCGCTA (SEQ ID NO:86) and UAGCGAUGCAGGAAAGGGU (SEQ ID NO:87), AGGGAACCCATCTCGGCAT (SEQ ID NO:88) and AUGCCGAGAUGGGUUCCCU (SEQ ID NO:89), GCATCCCTCATGGCCCCAA (SEQ ID NO:90) and UUGGGGCCAUGAGGGAUGC (SEQ ID NO:91), ACAAGCCTTTCCGCCTCCC (SEQ ID NO:92) and GGGAGGCGGAAAGGCUUGU (SEQ ID NO:93),CTGGATTATGGTGGCCTGA (SEQ ID NO: 94) and UCAGGCCACCAUAAUCCAG (SEQ ID NO: 95), CAGTCCTGATGCCGCCGAG (SEQ ID NO: 96) and CUCGGCGGCAUCAGGACUG (SEQ ID NO: 97), CGCCGCCTGGACCGGGAAC (SEQ ID NO: 98) and GUUCCCGGUCCAGGCGGCG (SEQ ID NO: 99), GGGCACCGACCTGGTGAGC (SEQ ID NO: 100) and GCUCACCAGGUCGGUGCCC (SEQ ID NO: 101), TATGTGGAGATGACCGTAG (SEQ ID NO: 102) and CUACGGUCAUCUCCACAUA (SEQ ID NO: 103), GAGGGGAAAGTCCGGCCAG (SEQ ID NO: 104) and CUGGCCGGACUUUCCCCUC (SEQ ID NO: 105), or CCCTACACCCAGGGCAAGT (SEQ ID NO: 106) and ACUUGCCCUGGGUGUAGGG (SEQ ID NO: 107), or a sense pair and an antisense pair selected from combinations thereof.

[0401] In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from SEQ ID NOs: 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, and 106. In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from AACGTCACTGTGCGTGCCA (SEQ ID NO: 70), CGGGAGACCGACGAGGAAT (SEQ ID NO: 72), GGAGGAGCCTGGCCGGAGA (SEQ ID NO: 74), TCCGGCTGCCCCTTCGCAG (SEQ ID NO: 76), and GGAGCCCGGAGTCCCTGTC (SEQ ID NO: 78) or combinations thereof.

[0402] In some embodiments, the double-stranded oligonucleotide construct comprises a sense and antisense pair selected from: #038, #089, #001, #101, #096, #102, #121, #103, #011, #097, #008 and #095, or combinations thereof (or pairs selected from Table 2C, Table 2D, Table 2E, Table 2F and Table 2G). In some embodiments, the compound comprises two or more oligonucleotides, and one of the oligonucleotides comprises a sense and antisense pair selected from TGGGACTTTAGGGCTAACC (SEQ ID NO: 108) and GGUUAGCCCUAAAGUCCCA (SEQ ID NO: 109), TGGGGTGATCAGCCCAAAA (SEQ ID NO: 110) and UUUUGGGCUGAUCACCCCA (SEQ ID NO: 111), CGCCGGCCTCCAGAACGCG (SEQ ID NO: 112) and CGCGUUCUGGAGGCCGGCG (SEQ ID NO: 113), ATTGCTTGCGTTGTGGGGG (SEQ ID NO: 114) and CCCCCACAACGCAAGCAAU (SEQ ID NO: 115), GGTGGGCTAGATAGATAGG (SEQ ID NO: 116) and CCUAUCUAUCUAGCCCACC (SEQ ID NO: 117), GGAGGAGGAACACATTAAG (SEQ ID NO: 118) and CUUAAUGUGUUCCUCCUCC (SEQ ID NO: 119), GGGCATGATCTCCAGTGCT (SEQ ID NO: 120) and AGCACUGGAGAUCAUGCCC (SEQ ID NO: 121), AAAGGGAGGTCTTGGAGTG (SEQ ID NO: 122) and CACUCCAAGACCUCCCUUU (SEQ ID NO: 123), GGCAAAACCGGGGCGAAGA (SEQ ID NO: 124) and UCUUCGCCCCGGUUUUGCC (SEQ ID NO: 125), TACAATTGGCCTGGTTCCT (SEQ ID NO: 126) and AGGAACCAGGCCAAUUGUA (SEQ ID NO: 127), GCTCGTGTGGCCAGCAAAG (SEQ ID NO: 128) and CUUUGCUGGCCACACGAGC (SEQ ID NO: 129), or GAGCCAATGTCTTTGGGTG (SEQ ID NO: 130) and CACCCAAAGACAUUGGCUC (SEQ ID NO: 131).

[0403] In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, and 130. In some embodiments, the oligonucleotide comprises a sense strand having a sequence with at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) sequence identity to a sequence selected from TGGGACTTTAGGGCTAACC (SEQ ID NO: 108), TGGGGTGATCAGCCCAAAA (SEQ ID NO: 110), CGCCGGCCTCCAGAACGCG (SEQ ID NO: 112), ATTGCTTGCGTTGTGGGGG (SEQ ID NO: 114), and GGTGGGCTAGATAGATAGG (SEQ ID NO: 116).

[0404] In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having a sense strand selected from Table 2C. In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having an antisense strand selected from Table 2C.

[0405] In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having a sense strand selected from Table 2D. In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having an antisense strand selected from Table 2D.

[0406] In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having a sense strand selected from Table 2E. In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having an antisense strand selected from Table 2E.

[0407] In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having a sense strand selected from Table 2F. In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having an antisense strand selected from Table 2F.

[0408] In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having a sense strand selected from Table 2G. In some embodiments, the double-stranded oligonucleotide comprises an oligonucleotide having an antisense strand selected from Table 2G.

[0409] Double-stranded oligonucleotide structure In one aspect, a double-stranded oligonucleotide structure comprising the structure of Formula 1 below is provided herein. A-X-R-Y-B [Formula 1]

[0410] In Formula 1, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y each independently represent a single covalent bond or a linker-mediated covalent bond, R refers to a double-stranded oligonucleotide comprising a sense strand and an antisense strand containing a sequence complementary thereto, and a monosaccharide is attached to the A or B terminus.

[0411] The monosaccharide may be, for example, glucose, fructose or galactose, and specifically may be glucose.

[0412] The monosaccharide may be specifically bound to the A terminus of the hydrophilic moiety A. For example, the monosaccharide may be glucose, and glucose is bound to the A terminus of the hydrophilic moiety A.

[0413] Accordingly, the present disclosure may be a structure containing a ligand, such as a monosaccharide, for improving the BBB permeability of the structures of Formula 1 to Formula 3', Formula 6 and Formula 7 shown below, and may have the structure of Formula 14. (L i )-A-X-R-Y-B [Formula 14]

[0414] In the above formula 14, A, B, X and Y are as defined in the above formula 1, L is a monosaccharide, i is an integer from 1 to 10, specifically an integer from 2 to 8, and more specifically 6.

[0415] A and L i may be linked by a linker. The linker may have, for example, the formula NH(CH2)nCONH-CH2-CH(OH)-CH2-.

[0416] Specifically, the double-stranded oligonucleotide structure according to the present disclosure may be an oligonucleotide structure containing a hydrophilic group and a hydrophobic group linked by a linker to the 6th carbon of glucose, and may be self-assembled.

[0417] The oligonucleotide structure can self-assemble, and "self-assembly" means that the structure can self-assemble into a group having an organized structure or pattern showing specific functionality.

[0418] As used herein, "double-stranded oligonucleotide" refers to a nucleic acid molecule that can mediate RNA inhibition or gene silencing via "siRNA", thereby specifically inhibiting the expression and / or activity of a target gene.

[0419] As used herein, "specificity" refers to the ability to specifically inhibit only the target gene without affecting other genes in the cell.

[0420] In some embodiments, the double-stranded oligonucleotide structure includes a sense strand and an antisense strand containing a sequence complementary thereto.

[0421] In some embodiments, the sense strand or the antisense strand may be characterized by being composed of 19 to 31 nucleotides, but is not limited thereto. In some cases, the sense strand or the antisense strand may further include 19 to 31 nucleotides, but is not limited thereto.

[0422] In some embodiments, the sense strand or the antisense strand may independently be DNA or RNA, and may be characterized in that, for example, they may include RNA / RNA, DNA / DNA, or DNA / RNA hybrid sequences.

[0423] In some embodiments, the sense strand or the antisense strand may be characterized by including chemical modifications, which may be, but are not limited to, at least one of the following:

[0424] A modification in which the hydroxy group (-OH) at the 2'-carbon position of the sugar structure in the nucleotide is substituted with any one selected from the group consisting of a methyl group (-CH3), a methoxy group (-OCH3), an amine group (-NH2), fluorine (-F), an O-2-methoxyethyl group, an O-propyl group, an O-2-methylthioethyl group, an O-3-aminopropyl group, an O-3-dimethylaminopropyl group, an O-N-methylacetamino group, and an O-dimethylamidooxyethyl group;

[0425] A modification in which the oxygen in the sugar structure of the nucleotide is substituted with sulfur;

[0426] A modification in which the nucleotide bond becomes any one selected from the group consisting of a phosphorothioate bond, a boranophosphate bond, and a methylphosphonate bond; and

[0427] Modifications to PNA (peptide nucleic acid), LNA (locked nucleic acid), or UNA (unlocked nucleic acid) forms.

[0428] In some embodiments, the chemical modifications may be for improving in vivo stability, or may contribute to conferring nuclease resistance and reducing non-specific immune responses.

[0429] In some embodiments, the double-stranded oligonucleotide structure is characterized in that at least one phosphate group is attached to the 5' end of the antisense strand, preferably 1 to 3 phosphate groups are attached, but the present disclosure is not limited thereto.

[0430] In some embodiments, the double-stranded oligonucleotides provided herein are a concept encompassing all substances having RNAi activity, and it is obvious to those skilled in the art that target gene-specific double-stranded oligonucleotides include target gene-specific shRNAs and the like. That is, the oligonucleotide may be characterized as being siRNA, shRNA or miRNA.

[0431] In some embodiments, the double-stranded oligonucleotide according to the present disclosure may include an overhang, which is a structure containing one or more unpaired nucleotides at the 3' end of one or both strands.

[0432] In some embodiments, the form of the double-stranded oligonucleotide according to the present disclosure is preferably a DNA-RNA hybrid, siRNA (short interfering RNA), shRNA (short hairpin RNA), miRNA (microRNA), etc., but the present disclosure is not limited thereto, and includes single-stranded miRNA inhibitors that can function as antagonists to miRNAs.

[0433] In some embodiments, further, in the above formula 14, the hydrophilic moiety A may be a hydrophilic block according to the following formulas 4 and 5.

[0434] In some embodiments, the double-stranded oligonucleotide structure according to the present disclosure may include the structure of the following formula 2. A-X-S-Y-B AS [Formula 2]

[0435] In some embodiments, in Formula 2, S and AS refer to the sense strand and the antisense strand of a double-stranded oligonucleotide, and the definitions of A, B, X, and Y are the same as those in Formula 1.

[0436] In some embodiments, more preferably, the pharmaceutical composition according to the present disclosure includes the structure of the following Formula 3. A-X-5’S 3’-Y-B AS [Formula 3]

[0437] In some embodiments, alternatively, the double-stranded oligonucleotide according to the present disclosure includes the structure of the following Formula 3'. A-X-3’S 5’-Y-B AS [Formula 3']

[0438] In some embodiments, in the above Formula 3 and Formula 3', the definitions of A, B, X, Y, S, and AS are the same as those in Formula 2, and 5' and 3' refer to the 5' and 3' ends of the sense strand.

[0439] In some embodiments, the molecular weight of the hydrophilic moiety can be, but is not limited to, 200 to 10,000.

[0440] In some embodiments, the hydrophilic moiety can be selected from, but is not limited to, the group consisting of polyethylene glycol (PEG), polyvinylpyrrolidone, and polyoxazoline.

[0441] In some embodiments, the hydrophilic moiety can be characterized by having the structure of the following Formula 4 or Formula 5. (A’ m -J) n [Formula 4] (J-A’ m ) n [Formula 5]

[0442] In some embodiments, in the above formula 4, A' refers to a hydrophilic partial monomer, J refers to a linker that connects m hydrophilic monomers to each other or m hydrophilic monomers to siRNA, m is an integer from 1 to 15, n is an integer from 1 to 10, the hydrophilic monomer A' is any one compound selected from the following compounds 1 to 3, and the linker (J) is PO3 - , SO3 and CO2.

Chemical formula

[0443] In some embodiments, in the above compound 1, G is selected from the group consisting of CH2, O, S and NH.

Chemical formula

Chemical formula

[0444] In some embodiments, when there is a hydrophilic block such as the above formula 4 or formula 5, the double-stranded oligonucleotide structure according to the present disclosure may have the structure of the following formula 6 or formula 7. (A’ m -J) n -X-R-Y-B [Formula 6] (J-A’ m ) n -X-R-Y-B [Formula 7]

[0445] In some embodiments, in the above formulas 6 and 7, the definitions of X, R, Y and B are the same as those in formula 1, and the definitions of A’, J, m and n are the same as those in formulas 4 and 5.

[0446] In some embodiments, in the above formulas 4 and 5, the hydrophilic monomer (A') can be any monomer of a nonionic hydrophilic polymer that meets the objectives of the present disclosure, preferably a monomer selected from Compounds 1 to 3 listed in Table 1, more preferably a monomer of Compound 1, and even more preferably G of Compound 1 can be selected from O, S, and NH.

[0447] In some embodiments, particularly among the hydrophilic monomers, the monomer represented by Compound 1 has excellent biocompatibility with good biocompatibility and low induction of immune response, improves the in vivo stability of the double-stranded oligonucleotide contained in the structure according to Formula 6 or Formula 7, and can improve the delivery efficiency. Therefore, various functional groups can be introduced, making it particularly suitable for the preparation of the structure according to the present disclosure.

Table 9

[0448] In some embodiments, preferably, in the above formulas 4 to 7, the total molecular weight of the hydrophilic moiety is in the range of 1,000 to 2,000. Therefore, for example, when using hexaethylene glycol related to Compound 1 in Formulas 6 and 7, that is, a substance where G is O and m is 6, since the molecular weight of hexaethylene glycol is 344, the number of repetitions is preferably 3 to 5. In particular, the present disclosure relates to (A' m -J) n or (J-A' m ) nThe number of hydrophilic groups represented by [hydrophilic group represented by , that is, the number of repetitions of the hydrophilic block, may be an appropriate number represented by n. The hydrophilic monomer A and the linker J contained in each hydrophilic block may be the same or different between each hydrophilic block. That is, when using three hydrophilic blocks (n = 3), by using the hydrophilic monomer related to compound 1 for the first block, the hydrophilic monomer related to compound 2 for the second block, and the hydrophilic monomer related to compound 3 for the third block, different hydrophilic monomers may be used in all hydrophilic blocks, or the same hydrophilic monomer selected from the hydrophilic monomers of compounds 1 to 3 may be used in all hydrophilic blocks. Similarly, for the linker that mediates the bonding of the hydrophilic monomers, the same linker may be used throughout all hydrophilic blocks, or different linkers may be used for each hydrophilic block. Also, the number m of hydrophilic monomers may be the same or different throughout all hydrophilic blocks. That is, three hydrophilic monomers are connected in the first hydrophilic block (m = 3), five hydrophilic monomers are connected in the second hydrophilic block (m = 5), four hydrophilic monomers are connected in the third hydrophilic block (m = 4), different numbers of hydrophilic monomers may be used, or the same number of hydrophilic monomers may be used throughout all hydrophilic blocks.

[0449] In some embodiments, further, in the present disclosure, when the linker (J) is preferably selected from the group consisting of -PO3 - -, -SO3-, and -CO2-, the present disclosure is not limited thereto, and it will be apparent to those skilled in the art that any linker suitable for the purpose of the present disclosure may be used depending on the hydrophilic monomer used.

[0450] In some embodiments, in the above formulas 1 to 3, formula 6 and formula 7, the hydrophobic moiety (B) serves to form nanoparticles composed of a double-stranded oligonucleotide structure through hydrophobic interaction. Preferably, the molecular weight of the hydrophobic moiety is 250 to 1,000, and it can be any one selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycol, C 12 ~C 50 unsaturated or saturated hydrocarbons, diacyl phosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols and tocotrienols, but is not limited thereto, and it is obvious to those skilled in the art that any hydrophobic moiety suitable for the purpose of the present disclosure can be used.

[0451] In some embodiments, the steroid derivative may be selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, copesteranyl formate and cholestanyl amine, and the glyceride derivative may be mono-, di- and tri-glycerides, and the fatty acid of the glyceride is preferably C 12 ~C 50 unsaturated or saturated fatty acids.

[0452] In some embodiments, in particular, among the hydrophobic moieties, saturated or unsaturated hydrocarbons or cholesterol are preferred in that they have the advantage of being easily combined in the synthesis process of the oligonucleotide structure according to the present disclosure, and most preferably C 24 hydrocarbons, especially in a form containing a disulfide bond. In some embodiments, the hydrophobic moiety contains C 24 (C6-S-S-C 18 ).

[0453] In some embodiments, the hydrophobic material is attached to the distal end of the hydrophilic material and can be attached at any position of the sense strand or antisense strand of the miRNA.

[0454] In some embodiments, the hydrophilic moieties, hydrophilic moiety blocks or hydrophobic moieties and double-stranded oligonucleotides of Formulas 1 to 3', Formula 6, Formula 7 and Formula 14 are linked by simple covalent bonds or linker-mediated covalent bonds (X or Y). The linker is not particularly limited as long as it binds covalently between the hydrophilic or hydrophobic moiety and the end of the double-stranded oligonucleotide and provides a bond that can be cleaved under specific circumstances if necessary. Thus, as the linker, any compound that binds and activates the double-stranded oligonucleotide and / or the hydrophilic moiety (or hydrophobic moiety) during the process of preparing the double-stranded oligonucleotide structure according to the present disclosure can be used. The covalent bond may be a non-cleavable bond or a cleavable bond. Here, the non-cleavable bond includes an amide bond or a phosphorylated bond, and the cleavable bond includes, but is not limited to, a disulfide bond, an acid-cleavable bond, an ester bond, an anhydride bond, a biodegradable bond or an enzyme-cleavable bond.

[0455] In some embodiments, in a structure comprising a double-stranded oligonucleotide according to the present disclosure, an additional amine group or polyhistidine group can be introduced at the end opposite to the end to which the hydrophilic moiety in the structure is bound.

[0456] In some embodiments, this is to facilitate the introduction of the structure carrier comprising the double-stranded oligonucleotide according to the present disclosure into cells and its endosomal escape. The introduction of amine groups and polyhistidine groups has been reported to facilitate the introduction of carriers such as quantum dots, dendrimers and liposomes into cells and their endosomal avoidance, as well as their advantages.

[0457] In some embodiments, specifically, the primary amine group modified at the end or outside of the carrier forms a conjugate with the negatively charged gene through electrostatic interaction while being protonated at the in vivo pH. It is known that after introduction into cells, the internal tertiary amine with a buffering effect at the low pH of endosomes promotes endosome leakage, so the carrier can be protected from lysosomal degradation. (Inhibition of gene transfer and expression using a polymer-based hybrid material. Polymer Sci. Technol., Vol. 23, No. 3, pp. 254-259).

[0458] In some embodiments, the non-essential amino acid histidine has an imidazole ring (pK R 6.04) in the residue (-R) and has the effect of increasing the buffering ability in endosomes and lysosomes. It is well known that histidine modification can be used to improve the endosome avoidance efficiency in non-viral gene carriers such as liposomes (Novel histidine-conjugated galactosylated cationic liposomes for efficient hepatocyte selective gene transfer in human hepatoma HepG2 cells. J. Controlled Release 118, pp. 262-270).

[0459] In some embodiments, the amine group or polyhistidine group may be connected to a hydrophilic moiety or hydrophilic block via one or more linkers.

[0460] In some embodiments, when the amine group or polyhistidine group is introduced into the hydrophilic moiety of the double-stranded oligonucleotide structure according to Formula 1 of the present disclosure, it may have the structure of Formula 8. P-J1-J2-A-X-R-Y-B [Formula 8]

[0461] In some embodiments, in Formula 8, the definitions of A, B, R, X, and Y are the same as those in Formula 1.

[0462] In some embodiments, P is an amine group or a polyhistidine group, J1 and J2 are linkers, and J1 and J2 can be independently selected from, but are not limited to, simple covalent bonds, O3 - , SO3, CO2, C 2~12 alkyl, alkenyl, and alkynyl. It will be apparent to those skilled in the art that J1 and J2 can be any linker suitable for the purposes of the present disclosure, depending on the type of hydrophilic moiety used.

[0463] In some embodiments, preferably, when an amine group is introduced, J2 is a simple covalent bond or PO3 - and J1 is preferably C6 alkyl, but these are not limited thereto.

[0464] In some embodiments, further, when a polyhistidine group is introduced, J2 is preferably a simple covalent bond or PO3 - and J1 is preferably Compound 4, but these are not limited thereto. [Chemical formula] Compound 4

[0465] In some embodiments, further, the hydrophilic moiety of the double-stranded oligonucleotide of Formula 8 is a hydrophilic block of Formula 5 or Formula 6, and when an amine group or a polyhistidine group is introduced, it may have the structure of Formula 9 or Formula 10. P-J1-J2-(A’ m -J) n -X-R-Y-B [Formula 9] P-J1-J2-(J-A’ m ) n -X-R-Y-B [Formula 10]

[0466] In some embodiments, in the above formulas 9 and 10, the definitions of X, R, Y, B, A’, J, m, and n are the same as those in formulas 4 and 5, but the definitions of P, J1, and J2 are the same as those in formula 8.

[0467] In some embodiments, particularly, in the above formulas 9 and 10, the hydrophilic moiety is preferably attached to the 3’ end of the sense strand of the double-stranded oligonucleotide. In this case, the above formulas 8 to 10 may have the forms of the following formulas 11 to 13. P-J1-J2-A-X-3’ S 5’-Y-B AS [Formula 11] P-J1-J2-(A’ m -J) n -X-3’ S 5’-Y-B AS [Formula 12] P-J1-J2-(J-A’ m ) n -X-3’ S 5’-Y-B AS [Formula 13]

[0468] In some embodiments, in the above formulas 11 to 13, the definitions of X, R, Y, B, A, A’, J, m, n, P, J1, and J2 are the same as those in the above formulas 8 to 10, and 5’ and 3’ represent the 5’ end and the 3’ end of the sense strand of the target gene-specific double-stranded oligonucleotide.

[0469] In some embodiments, as the amine group that can be introduced in the present disclosure, primary to tertiary amines may be used, but the use of primary amines is particularly preferred. The introduced amine group may exist in the form of an amine salt. For example, the salt of a primary amine may exist in the form of NH3 + in the form.

[0470] In some embodiments, further, the polyhistidine group that can be introduced in the present disclosure preferably contains 3 to 10 histidines, more preferably 5 to 8, and most preferably 6 histidines. Further, one or more cysteines may be included in addition to histidine.

[0471] On the other hand, in some embodiments, when a targeting moiety is provided to a double-stranded oligonucleotide structure containing a target gene-specific double-stranded oligonucleotide according to the present disclosure and nanoparticles formed therefrom, this can efficiently promote delivery to target cells, thereby delivering to target cells and showing a strong target gene expression control effect even at a relatively low dose of administration.

[0472] In another aspect, nanoparticles containing a double-stranded oligonucleotide structure are provided herein. In the present disclosure, the double-stranded oligonucleotide structure may be characterized by forming self-assembled nanoparticles having a neutral charge with a size of 10 to 100 nm in an aqueous solution for administration.

[0473] In some embodiments, the nanoparticles may be characterized by being composed of a mixture of double-stranded oligonucleotide structures containing different sequences. In some embodiments, the nanoparticles contain a mixture of double-stranded oligonucleotide structures containing different sequences specific for different target molecules (e.g., different mRNA transcripts). In some embodiments, the nanoparticles contain a mixture of double-stranded oligonucleotide structures containing different sequence-specific different sites on a single target molecule (e.g., different target sites on a single mRNA transcript).

[0474] In some embodiments, the nanoparticles contain a mixture of double-stranded oligonucleotide structures containing two different sequences. In some embodiments, the nanoparticles contain a mixture of double-stranded oligonucleotide structures containing three or more different sequences.

[0475] When the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing different sequences on different target molecules, the different target molecules can be molecules involved in the same disease. When the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing different sequences on different target molecules, the different target molecules can be molecules involved in the same biological process (e.g., the same molecular pathway).

[0476] In some embodiments, the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing two different sequences, and the two different sequences target two different target molecules associated with Alzheimer's disease (see, for example, Table 6A). In some embodiments, the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing two different sequences, and the two different sequences target two different target molecules associated with Parkinson's disease (see, for example, Table 6B). In some embodiments, the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing two different sequences, and the two different sequences target two different target molecules associated with Huntington's disease (see, for example, Table 6C). In some embodiments, the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing two different sequences, and the two different sequences target two different target molecules associated with multiple sclerosis (see, for example, Table 6D). In some embodiments, the nanoparticles comprise a mixture of double-stranded oligonucleotide structures containing two different sequences, and the two different sequences target two different target molecules associated with spinal cord injury (see, for example, Table 6E).

[0477] In another aspect, provided herein is a composition for blood-brain barrier penetration, the composition comprising a double-stranded oligonucleotide structure.

[0478] Method of treatment In another aspect, a method of preventing or treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, wherein the disorder is associated with the expression and / or activity of one or more pathological genes, wherein the target molecule is one or more pathological genes, wherein the administration reduces or inhibits the expression and / or activity of the target molecule in the subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound provided herein, the nanoparticle provided herein, the composition provided herein, or the pharmaceutical composition provided herein, thereby alleviating or delaying one or more signs or symptoms of the disorder in the subject as compared to the subject before or without administration of the compound provided herein, the nanoparticle provided herein, the composition provided herein, or the pharmaceutical composition provided herein.

[0479] In another aspect, a method of alleviating or delaying one or more signs or symptoms of a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, wherein the disorder is associated with the expression and / or activity of one or more pathological genes, wherein the target molecule is one or more pathological genes, wherein the administration reduces or inhibits the expression and / or activity of the target molecule in the subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound provided herein, the nanoparticle provided herein, the composition provided herein, or the pharmaceutical composition provided herein.

[0480] In another aspect, a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker)) comprising administering a compound comprising the structure of a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof, the disorder is related to the expression and / or activity of one or more pathological genes, the target molecule is one or more pathological genes, the administration reduces or inhibits the expression and / or activity of the target molecule in the subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound, thereby alleviating or delaying one or more signs or symptoms of the disorder in the subject as compared to the subject before or without administration of the compound, a method is provided herein.

[0481] A method of alleviating or delaying one or more signs or symptoms of a disorder in a subject in need of treatment for the disorder, the method comprising administering to the subject a therapeutically effective amount of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker)) comprising administering a compound comprising the structure of a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the terminus of A, the terminus of B, or a combination thereof)) A method wherein administration reduces or inhibits the expression and / or activity of a target molecule in a subject as compared to the expression and / or activity of the target molecule in the subject before or without administration of the compound, thereby alleviating or delaying one or more signs or symptoms of a disorder in the subject as compared to the subject before or without administration of the compound.

[0482] In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein alleviates or delays one or more signs or symptoms of a disorder in a subject as compared to the subject before or without such administration. In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein alleviates one or more signs or symptoms of a disorder in a subject as compared to the subject before or without such administration. In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein delays one or more signs or symptoms of a disorder in a subject as compared to the subject before or without such administration.

[0483] In some embodiments, administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein alleviates one or more signs or symptoms of a disorder in a subject by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to the subject before or without such administration. In some embodiments, administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein alleviates one or more signs or symptoms of a disorder in a subject by at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 1500-fold, about 2000-fold, about 2500-fold, about 3000-fold, about 3500-fold, about 4000-fold, about 4500-fold, about 5000-fold, about 5500-fold, about 6000-fold, about 6500-fold, about 7000-fold, about 7500-fold, about 8000-fold, about 8500-fold, about 9000-fold, about 9500-fold, about 10000-fold (10000 - folds - folds), about 20000-fold, about 30000-fold, about 40000-fold, or about 50000-fold, compared to the subject before or without such administration.

[0484] In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein delays one or more signs or symptoms of a disorder in a subject by at least about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days compared to the subject before or without such administration.

[0485] In some embodiments, the disorder is a neuropathy. A compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein can be used in a composition for treating or improving a neurological disease (such as Alzheimer's disease, dementia, Parkinson's disease, etc.), and is expected to be useful as a composition for improving cognitive function / memory and preventing and treating neurological diseases by inhibiting the deposition of amyloid beta (Aβ), inhibiting brain inflammation, and inhibiting tau phosphorylation.

[0486]

[0486] In some embodiments, the neuropathy is Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman syndrome, Rett syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury.

[0487]

[0486] In some embodiments, the neuropathy is Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman syndrome, Rett syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, tauopathy, age-related macular degeneration, or traumatic brain injury.

[0488]

[0486] In some embodiments, the disorder is Alzheimer's disease and the target molecule is BACE1-AS, BACE1, presenilin 1 (PS1), ROCK-II, I2PP-2A, ACAT-1, Nogo receptor, mutant presenilin 1 (L392V PS-1), APP, Tau, VDAC1, or any combination thereof. In some embodiments, the disorder is Parkinson's disease and the target molecule is α-synuclein. In some embodiments, the disorder is Huntington's disease and the target molecule is huntingtin (Htt). In some embodiments, the disorder is multiple sclerosis and the target molecule is Notch1, LINGO-1, NR4A2, TRIF, caspase-2, CaMKII, or any combination thereof. In some embodiments, the disorder is spinal cord injury and the target molecule is glial fibrillary acidic protein (GFAP), vimentin, EphB3, iNOS, Nischarin, RhoA, or any combination thereof.

[0489]

[0486] In some embodiments, the disorder is any one of the diseases or disorders listed in Table 6A, Table 6B, Table 6C, Table 6D, Table 6E or Table 5, and the target molecule is any one of the corresponding target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D or Table 6E.

[0490] In some embodiments, the disorder is cancer. In some embodiments, the cancer is brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, stomach cancer, colorectal cancer, or any combination thereof.

[0491] In some embodiments, the cancer is glioblastoma, non-small cell lung cancer, prostate cancer, pancreatic ductal adenocarcinoma, metastatic gastric adenocarcinoma, invasive ductal carcinoma of the breast, or colorectal cancer.

[0492] In some embodiments, the cancer is prostate cancer, lung cancer, kidney cancer, stomach cancer, colon cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, esophageal cancer, testicular cancer, liver cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, skin cancer, muscle cancer, cartilage cancer, bone cancer, endothelial cancer, epithelial cancer, dermal cancer, basal cancer, retinal cancer, skin cancer, or brain cancer.

[0493] In some embodiments, the cancer is leukemia, lymphoma, or myeloma. In some embodiments, the cancer is B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative state, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia, myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia or preleukemia.

[0494] In some embodiments, one or more signs or symptoms include Aβ peptide accumulation in the brain, tau peptide accumulation in the brain, phosphorylated tau accumulation in the brain, tau protein phosphorylation, hippocampal damage, cognitive deficits, or any combination thereof. In some embodiments, Aβ peptide accumulation occurs in the CA1 and uncus of the subject's brain. In some embodiments, tau peptide accumulation occurs in the CA1 and uncus of the subject's brain. In some embodiments, phosphorylated tau accumulation occurs in the CA1 and uncus of the subject's brain.

[0495] In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein results in any one or any combination of the effects listed in Table 6A, Table 6B, Table 6C, Table 6D, or Table 6E, for a subject with or without such administration.

[0496] In some embodiments, administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein does not show systemic toxicity comparable to or shows minimal systemic toxicity to a control subject with or without administration. In some embodiments, upon administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein, the subject shows systemic toxicity at a level of at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to a control subject with or without administration.

[0497] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject exhibits no hepatotoxicity or minimal hepatotoxicity comparable to a control subject before or without administration.

[0498] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject exhibits hepatotoxicity at a level of at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% relative to a control subject before or without administration.

[0499] In some embodiments, hepatotoxicity is evaluated by the alkaline phosphatase (ALP) level, by the alanine aminotransferase (ALT) level, by the aspartate aminotransferase (AST) level, by the total bilirubin (T-bil) level, by the ammonia (NH3) level, or by any combination thereof in a subject. In some embodiments, hepatotoxicity is evaluated by the alkaline phosphatase (ALP) level, by the alanine aminotransferase (ALT) level, by the aspartate aminotransferase (AST) level, by the total bilirubin (T-bil) level, by the ammonia (NH3) level, or by any combination thereof in a sample from a subject. In some embodiments, hepatotoxicity is evaluated by the alkaline phosphatase (ALP) level, by the alanine aminotransferase (ALT) level, by the aspartate aminotransferase (AST) level, by the total bilirubin (T-bil) level, by the ammonia (NH3) level, or by any combination thereof in a blood sample from a subject.

[0500] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the alkaline phosphatase (ALP) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the alkaline phosphatase (ALP) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0501] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the alanine aminotransferase (ALT) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration.

[0502] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the alanine aminotransferase (ALT) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0503] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the aspartate aminotransferase (AST) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the aspartate aminotransferase (AST) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0504] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the total bilirubin (T-bil) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the total bilirubin (T-bil) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0505] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the ammonia (NH3) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the ammonia (NH3) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0506] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject does not exhibit nephrotoxicity comparable to or exhibits minimal nephrotoxicity compared to a control subject before or without administration.

[0507] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject exhibits nephrotoxicity at a level of at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to a control subject before or without administration.

[0508] In some embodiments, nephrotoxicity is evaluated by lactate (Lac) levels, blood urea nitrogen (BUN) levels, creatinine (Crea) levels, or any combination thereof in the subject. In some embodiments, nephrotoxicity is evaluated by lactate (Lac) levels, blood urea nitrogen (BUN) levels, creatinine (Crea) levels, or any combination thereof in a sample from the subject. In some embodiments, nephrotoxicity is evaluated by lactate (Lac) levels, blood urea nitrogen (BUN) levels, creatinine (Crea) levels, or any combination thereof in a blood sample from the subject.

[0509] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the lactate (Lac) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the lactate (Lac) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0510] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the blood urea nitrogen (BUN) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the blood urea nitrogen (BUN) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0511] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the creatinine (Crea) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the creatinine (Crea) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0512] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject does not exhibit or exhibits minimal altered lipid metabolism comparable to a control subject before or without administration.

[0513] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject exhibits a change in lipid metabolism at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% levels compared to a control subject before or without administration.

[0514] In some embodiments, lipid metabolism is evaluated by lipase (Lip) levels, high density lipoprotein (HDL) levels, low density lipoprotein (LDL) levels, total cholesterol (T-Chol) levels, triglyceride (TG) levels, or any combination thereof in a subject. In some embodiments, lipid metabolism is evaluated by lipase (Lip) levels, high density lipoprotein (HDL) levels, low density lipoprotein (LDL) levels, total cholesterol (T-Chol) levels, triglyceride (TG) levels, or any combination thereof in a sample from a subject. In some embodiments, lipid metabolism is evaluated by lipase (Lip) levels, high density lipoprotein (HDL) levels, low density lipoprotein (LDL) levels, total cholesterol (T-Chol) levels, triglyceride (TG) levels, or any combination thereof in a blood sample from a subject.

[0515] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the lipase (Lip) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the lipase (Lip) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0516] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the high density lipoprotein (HDL) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the high density lipoprotein (HDL) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0517] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the low density lipoprotein (LDL) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the low density lipoprotein (LDL) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0518] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the total cholesterol (T-Chol) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the total cholesterol (T-Chol) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0519] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the triglyceride (TG) levels in a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the triglyceride (TG) levels in a sample from a subject are at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the levels in a sample from a control subject before or without administration.

[0520] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject does not exhibit or exhibits minimal altered calcium homeostasis comparable to a control subject before or without administration.

[0521] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the subject exhibits calcium homeostasis that is changed at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% levels compared to a control subject before or without administration.

[0522] In some embodiments, calcium homeostasis is evaluated by the calcium (Ca) level, the phosphorus (P) level or a combination thereof in the subject. In some embodiments, calcium homeostasis is evaluated by the calcium (Ca) level, the phosphorus (P) level or a combination thereof in a sample from the subject. In some embodiments, calcium homeostasis is evaluated by the calcium (Ca) level, the phosphorus (P) level or a combination thereof in a blood sample from the subject.

[0523] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the calcium (Ca) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the calcium (Ca) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0524] In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the phosphorus (P) level in a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a control subject before or without administration. In some embodiments, upon administration of the compounds provided herein, the nanoparticles provided herein, the compositions provided herein, or the pharmaceutical compositions provided herein, the phosphorus (P) level in a sample from a subject is at least about 100%, about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60% compared to the level in a sample from a control subject before or without administration.

[0525] In some embodiments, the blood-brain barrier penetration of a compound in a subject's brain is increased compared to the blood-brain barrier penetration of a compound having the same structure to which a ligand molecule for GLUT or a functional analog thereof is not linked.

[0526] In some embodiments, the blood-brain barrier permeability of a compound in the brain of a subject is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 800%, about 850%, about 900%, about 1000%, about 1500%, about 2000%, about 2500%, about 3000%, about 3500%, about 4000%, about 4500%, about 5000%, about 5500%, about 6000%, about 6500%, about 7000%, about 7500%, about 8000%, about 8500%, about 9000%, about 9500%, about 10000%, about 15000%, about 20000%, about 25000%, about 30000%, about 35000%, about 40000%, about 45000%, about 50000%, about 55000%, about 60000%, about 65000%, about 70000%, about 75000%, about 80000%, about 85000%, about 90000%, about 100000% or more increased compared to the blood-brain barrier permeability of a compound having the same structure that does not have a ligand molecule or a functional analog thereof for the linked GLUT.In some embodiments, the blood-brain barrier permeability of the compound in the subject's brain is increased by at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 1500-fold, about 2000-fold, about 2500-fold, about 3000-fold, about 3500-fold, about 4000-fold, about 4500-fold, about 5000-fold, about 5500-fold, about 6000-fold, about 6500-fold, about 7000-fold, about 7500-fold, about 8000-fold, about 8500-fold, about 9000-fold, about 9500-fold, about 10000-fold (10000 - folds - folds), about 20000-fold, about 30000-fold, about 40000-fold, about 50000-fold, 60000-fold, about 70000-fold, about 80000-fold, about 90000-fold, about 100000-fold or more compared to the blood-brain barrier permeability of a compound having the same structure that does not have a ligand molecule for GLUT or a functional analog thereof.

[0527] In some embodiments, the retention time and / or distribution of the compound in the subject's brain is increased compared to the retention time and / or distribution of a compound having the same structure to which a ligand molecule for GLUT or a functional analog thereof is not linked.

[0528] In some embodiments, the retention time and / or distribution of a compound in the brain of a subject is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 800%, about 850%, about 900%, about 1000%, about 1500%, about 2000%, about 2500%, about 3000%, about 3500%, about 4000%, about 4500%, about 5000%, about 5500%, about 6000%, about 6500%, about 7000%, about 7500%, about 8000%, about 8500%, about 9000%, about 9500%, about 10000%, about 15000%, about 20000%, about 25000%, about 30000%, about 35000%, about 40000%, about 45000%, about 50000%, about 55000%, about 60000%, about 65000%, about 70000%, about 75000%, about 80000%, about 85000%, about 90000%, about 100000% or more increased compared to the retention time and / or distribution of a compound having the same structure that does not have a ligand molecule or a functional analog thereof linked to GLUT.In some embodiments, the retention time and / or distribution of the compound in the brain of the subject is at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 1500-fold, about 2000-fold, about 2500-fold, about 3000-fold, about 3500-fold, about 4000-fold, about 4500-fold, about 5000-fold, about 5500-fold, about 6000-fold, about 6500-fold, about 7000-fold, about 7500-fold, about 8000-fold, about 8500-fold, about 9000-fold, about 9500-fold, about 10000-fold (10000 - folds - folds), about 20000-fold, about 30000-fold, about 40000-fold, about 50000-fold, 60000-fold, about 70000-fold, about 80000-fold, about 90000-fold, about 100000-fold or more increased compared to the retention time and / or distribution of a compound having the same structure that does not have a ligand molecule or a functional analog thereof for the linked GLUT.

[0529] In some embodiments, the compound is specifically delivered by one or more tissues, organs or cells that express GLUT as compared to tissues, organs or cells that do not express GLUT.

[0530] In some embodiments, the compound is delivered to one or more tissues, organs, or cells that express GLUT to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 800%, about 850%, about 900%, about 1000%, about 1500%, about 2000%, about 2500%, about 3000%, about 3500%, about 4000%, about 4500%, about 5000%, about 5500%, about 6000%, about 6500%, about 7000%, about 7500%, about 8000%, about 8500%, about 9000%, about 9500%, about 10000%, about 15000%, about 20000%, about 25000%, about 30000%, about 35000%, about 40000%, about 45000%, about 50000%, about 55000%, about 60000%, about 65000%, about 70000%, about 75000%, about 80000%, about 85000%, about 90000%, about 100000% or more, compared to tissues, organs, or cells that do not express GLUT.In some embodiments, the compound is delivered to one or more tissues, organs, or cells that express GLUT to a greater extent, at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 1500-fold, about 2000-fold, about 2500-fold, about 3000-fold, about 3500-fold, about 4000-fold, about 4500-fold, about 5000-fold, about 5500-fold, about 6000-fold, about 6500-fold, about 7000-fold, about 7500-fold, about 8000-fold, about 8500-fold, about 9000-fold, about 9500-fold, about 10000-fold (10000 - folds - folds), about 20000-fold, about 30000-fold, about 40000-fold, about 50000-fold, 60000-fold, about 70000-fold, about 80000-fold, about 90000-fold, about 100000-fold or more, compared to tissues, organs, or cells that do not express GLUT.

[0531] In some embodiments, the expression and / or activity of the target molecule is regulated to a greater extent in one or more tissues, organs, or cells that express GLUT, compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the expression of the target molecule is regulated to a greater extent in one or more tissues, organs, or cells that express GLUT, compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the target molecule expression is regulated in one or more tissues, organs, or cells that express GLUT to a greater extent, at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to tissues, organs, or cells that do not express GLUT.

[0532] In some embodiments, the activity of the target molecule is regulated to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the target molecule activity is regulated to a greater extent in one or more tissues, organs, or cells that express GLUT by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100% as compared to tissues, organs, or cells that do not express GLUT.

[0533] In some embodiments, the expression and / or activity of the target molecule is reduced or inhibited to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT.

[0534] In some embodiments, the expression of the target molecule is reduced or inhibited to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the expression of the target molecule is reduced or inhibited to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the target molecule expression is regulated to a greater extent in one or more tissues, organs, or cells that express GLUT by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100% as compared to tissues, organs, or cells that do not express GLUT.

[0535] In some embodiments, the activity of the target molecule is reduced or inhibited to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT. In some embodiments, the target molecule activity is reduced or inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100% to a greater extent in one or more tissues, organs, or cells that express GLUT as compared to tissues, organs, or cells that do not express GLUT.

[0536] In some embodiments, one or more tissues, organs, or cells that express GLUT include brain, blood, brain, intestine, liver, kidney, pancreas, embryo, testis, placenta, muscle, heart, fat, adipose tissue, spleen, colon, prostate, testis, blastocyst, skeletal muscle, white adipose tissue, brown adipose tissue, or any combination thereof.

[0537] In some embodiments, (i) GLUT is GLUT1, and one or more tissues, organs, or cells that express GLUT include brain, blood, or a combination thereof; (ii) GLUT is GLUT2, and one or more tissues, organs, or cells that express GLUT include brain, intestine, liver, kidney, pancreas, or any combination thereof; (iii) GLUT is GLUT3, and one or more tissues, organs, or cells that express GLUT include brain, embryo, testis, placenta, or any combination thereof; (iv) GLUT is GLUT4, and one or more tissues, organs, or cells that express GLUT include brain, muscle, heart, fat, adipose tissue, or any combination thereof; (v) GLUT is GLUT5, and one or more tissues, organs, or cells that express GLUT include brain, intestine, testis, muscle, kidney, fat, or any combination thereof; (vi) The GLUT is GLUT6, and one or more tissues, organs, or cells that express GLUT include the brain, spleen, or a combination thereof; (vii) The GLUT is GLUT7, and one or more tissues, organs, or cells that express GLUT include the intestine, colon, prostate, testis, prostate, or any combination thereof; (viii) The GLUT is GLUT8, and one or more tissues, organs, or cells that express GLUT include the brain, testis, liver, spleen, fat, blastocyst, or any combination thereof; (ix) The GLUT is GLUT9, and one or more tissues, organs, or cells that express GLUT include the liver, kidney, intestine, colon, or any combination thereof; (x) The GLUT is GLUT10, and one or more tissues, organs, or cells that express GLUT include the liver, pancreas, fat, skeletal muscle, heart, adipose tissue, placenta, kidney, or any combination thereof; (xi) The GLUT is GLUT11, and one or more tissues, organs, or cells that express GLUT include the heart, muscle, kidney, pancreas, placenta, or any combination thereof; (xii) The GLUT is GLUT12, and one or more tissues, organs, or cells that express GLUT include the brain, muscle, heart, fat, pancreas, prostate, adipose tissue, placenta, kidney, or any combination thereof; (xiii) The GLUT is GLUT13, and one or more tissues, organs, or cells that express GLUT include the brain, white adipose tissue, brown adipose tissue, kidney, or any combination thereof; or (xiv) The GLUT is GLUT14, and one or more tissues, organs, or cells that express GLUT include the testis.

[0538] In some embodiments, (i) the GLUT is GLUT1, and one or more tissues, organs, or cells that express GLUT include the blood-brain barrier, astrocytes, erythrocytes, or any combination thereof; (ii) The GLUT is GLUT2, and one or more tissues, organs, or cells that express GLUT include astrocytes, the gastrointestinal tract, the small intestine, intestinal absorptive epithelial cells, hepatocytes, pancreatic β-cells, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus nerve, the paraventricular nucleus of the hypothalamus, the lateral hypothalamic area, the arcuate nucleus, and the olfactory bulb, or any combination thereof; (iii) The GLUT is GLUT3, and one or more tissues, organs, or cells that express GLUT include neurons, the blood-brain barrier, astrocytes, sperm, spermatozoa, fibroblasts, platelets, retinal endothelial cells, leukocytes, or any combination thereof; (iv) The GLUT is GLUT4, and one or more tissues, organs, or cells that express GLUT include neurons, adipocytes, skeletal muscle cells, cardiomyocytes, the hypothalamus, the cerebellum, the cortex, and the hippocampus, or combinations thereof; (v) The GLUT is GLUT5, and one or more tissues, organs, or cells that express GLUT include microglia, the blood-brain barrier, the small intestine, the apical membrane of intestinal cells, the plasma membrane of mature sperm, skeletal muscle, or any combination thereof; (vi) The GLUT is GLUT6, and one or more tissues, organs, or cells that express GLUT include leukocytes, peripheral leukocytes, germ cells of the testis, or any combination thereof; (vii) The GLUT is GLUT7, and one or more tissues, organs, or cells that express GLUT include the small intestine; (viii) The GLUT is GLUT8, and one or more tissues, organs, or cells that express GLUT include neurons, brown adipose tissue, the cerebellum, the adrenal gland, spermatocytes, mature sperm, or any combination thereof; (ix) The GLUT is GLUT9, and one or more tissues, organs, or cells that express GLUT include the small intestine, leukocytes, chondrocytes, or any combination thereof; (x) The GLUT is GLUT10, and one or more tissues, organs, or cells that express GLUT include white fat; (xi) The GLUT is GLUT12, and one or more tissues, organs, or cells that express GLUT include astrocytes, prostate, small intestine, chondrocytes, or any combination thereof; or (xii) The GLUT is GLUT13, and one or more tissues, organs, or cells that express GLUT include neurons.

[0539] In some embodiments, one or more tissues, organs, or cells that express GLUT include cancer cells.

[0540] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, gastric cancer, colorectal cancer, and any combination thereof.

[0541] In some embodiments, (i) the GLUT is GLUT1, and the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, and any combination thereof; (ii) the GLUT is GLUT3, and the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, cervical cancer, kidney cancer, lung cancer, glioblastoma, and any combination thereof; (iii) the GLUT is GLUT5, and the cancer is selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, leukemia, and any combination thereof; (iv) the GLUT is GLUT10, and the cancer is leukemia; (v) the GLUT is GLUT12, and the cancer is breast cancer; or (vi) the GLUT is GLUT14, and the cancer is brain cancer.

[0542] In some embodiments, one or more tissues, organs, or cells that express GLUT include any one of the tissues, organs, or cells listed in Table 4 or Table 5, or any combination thereof.

[0543] In some embodiments, (i) the target molecule is BACE1-AS and administration results in improvement of memory and learning behaviors; (ii) the target molecule is BACE1 and administration results in a decrease in amyloid plaque rate, improvement of neuropathological and behavioral symptoms, suppression of BACE1 expression and / or activity, reduction of plaque burden in the cerebral cortex and hippocampus, increase in the level of synaptophysin, relief of memory loss, or any combination thereof; (iii) the target molecule is presenilin 1 (PS1) and administration results in a reduction in the level of Aβ42; (iv) the target molecule is ROCK-II and administration results in promotion of axonal regeneration; (v) the target molecule is I2 PP-2A and administration results in a decrease in the levels of Aβ, APP, and phosphorylated tau, improvement of memory and learning ability, or a combination thereof; (vi) the target molecule is ACAT-1 and administration results in reduction of the enzymatic process of APP, enhancement of the level of free cholesterol, or a combination thereof; (vii) the target molecule is the Nogo receptor and administration results in promotion of the regeneration and repair of cholinergic neurons; (viii) the target molecule is mutant presenilin 1 (L392V PS-1), BACE1, or a combination thereof and administration results in a decrease in amyloid plaque levels; (ix) the target molecule is APP, Tau, VDAC1, or a combination thereof and administration results in improvement of synaptic activity and mitochondrial function; (x) the target molecule is α-synuclein (SNCA) and administration results in a reduction in SNCA levels, reduction of hSNCA-mediated behavioral deficits, improvement in motor dysfunction, cell protection from cell death by apoptosis, reduction of α-syn accumulation, improvement of inflammatory pathologies, or any combination thereof; (xi) The target molecule is Htt, and administration results in inhibition of Htt expression and / or activity, reduction in the size and number of neuronal intranuclear inclusions (NII), improvement of motor deficits, survival of neurons, reduction in the level of mutant htt protein, or any combination thereof; (xii) The target molecule is T-bet, and administration results in regulation of interferon (IFN), prevention of disease onset, or a combination thereof; (xiii) The target molecule is Notch1, and administration results in improved motor function, repair in histopathological sections, or a combination thereof; (xiv) The target molecule is LINGO-1, and administration results in improvement of memory and learning behaviors; (xv) The target molecule is NR4A2, and administration results in inhibition of the pathogenic potential of IFN and IL-17; (xvi) The target molecule is TRIF, and administration results in alleviation of disease severity through inhibition of interleukin and cytokine release; (xvii) The target molecule is caspase-2, and administration results in inhibition of neuronal loss, reduction in the thickness of the retinal nerve fiber layer (RNFL), increase in the survival of retinal ganglion cells (RGC), or any combination thereof; (xviii) The target molecule is CaMKII, and administration results in reduction of mechanical and thermal hypersensitivity, reduction of evoked and non-evoked pain, or a combination thereof; (xix) The target molecule is GFAP, vimentin, or a combination thereof, and administration results in improvement of urinary function; (xx) The target molecule is EphB3, and administration results in improvement of axonal regeneration, improvement of motor function, or a combination thereof; (xxi) The target molecule is iNOS, and administration results in improvement of secondary injury after spinal cord injury; (xxii) The target molecule is Nischarin, and administration results in improvement of motor function; or (xxiii) The target molecule is RhoA, and administration results in improvement of walking, reduction of allodynia, or a combination thereof.

[0544] In some embodiments, the target molecule is any one of the target molecules listed in Table 6A, Table 6B, Table 6C, Table 6D, or Table 6E, or any combination thereof, and administration of a compound provided herein, a nanoparticle provided herein, a composition provided herein, or a pharmaceutical composition provided herein results in any one of the effects listed in Table 6A, Table 6B, Table 6C, Table 6D, or Table 6E, or any combination thereof, as compared to a subject before or without such administration.

[0545] In some embodiments, the single dose of the compounds provided herein can be administered once a week or 1 to 3 times a week at 1 μg / kg to 100 mg / kg, preferably 5 μg / kg to 50 mg / kg, although the dosage and dosing interval are not limited thereto. In some embodiments, the single dose of the compounds provided herein is about 1 μg / kg to about 100 mg / kg, about 1 μg / kg to about 90 mg / kg, about 1 μg / kg to about 80 mg / kg, about 1 μg / kg to about 70 mg / kg, about 1 μg / kg to about 60 mg / kg, about 1 μg / kg to about 50 mg / kg, about 1 μg / kg to about 40 mg / kg, about 1 μg / kg to about 30 mg / kg, about 1 μg / kg to about 20 mg / kg, about 1 μg / kg to about 10 mg / kg, about 1 μg / kg to about 5 mg / kg, about 1 μg / kg to about 1 mg / kg, about 1 μg / kg to about 900 μg / kg, about 1 μg / kg to about 800 μg / kg, about 1 μg / kg to about 700 μg / kg, about 1 μg / kg to about 600 μg / kg, about 1 μg / kg to about 500 μg / kg, about 1 μg / kg to about 400 μg / kg, about 1 μg / kg to about 300 μg / kg, about 1 μg / kg to about 200 μg / kg, about 1 μg / kg to about 100 μg / kg, about 1 μg / kg to about 90 μg / kg, about 1 μg / kg to about 80 μg / kg, about 1 μg / kg to about 70 μg / kg, about 1 μg / kg to about 60 μg / kg, about 1 μg / kg to about 50 μg / kg, about 1 μg / kg to about 40 μg / kg, about 1 μg / kg to about 30 μg / kg, about 1 μg / kg to about 20 μg / kg, about 1 μg / kg to about 10 μg / kg, or about 1 μg / kg to about 5 μg / kg.In some embodiments, the single dose of the compounds provided herein can be from about 1 μg / kg to about 100 mg / kg, from about 5 μg / kg to about 100 mg / kg, from about 10 μg / kg to about 100 mg / kg, from about 20 μg / kg to about 100 mg / kg, from about 30 μg / kg to about 100 mg / kg, from about 40 μg / kg to about 100 mg / kg, 50 μg / kg to about 100 mg / kg, from about 60 μg / kg to about 100 mg / kg, from about 70 μg / kg to about 100 mg / kg, from about 80 μg / kg to about 100 mg / kg, from about 90 μg / kg to about 100 mg / kg, from about 100 μg / kg to about 100 mg / kg, from about 200 μg / kg to about 100 mg / kg, from about 300 μg / kg to about 100 mg / kg, from about 400 μg / kg to about 100 mg / kg, from about 500 μg / kg to about 100 mg / kg, from about 600 μg / kg to about 100 mg / kg, from about 700 μg / kg to about 100 mg / kg, from about 800 μg / kg to about 100 mg / kg, from about 900 μg / kg to about 100 mg / kg, from about 1 mg / kg to about 100 mg / kg, from about 5 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 100 mg / kg, from about 20 mg / kg to about 100 mg / kg, from about 30 mg / kg to about 100 mg / kg, from about 40 mg / kg to about 100 mg / kg, from about 50 mg / kg to about 100 mg / kg, from about 60 mg / kg to about 100 mg / kg, from about 70 mg / kg to about 100 mg / kg, from about 80 mg / kg to about 100 mg / kg, from about 90 mg / kg to about 100 mg / kg, or from about 100 mg / kg to about 100 mg / kg. In some embodiments, the single dose of the compounds provided herein can be from about 1 μg / kg to about 100 mg / kg, from about 5 μg / kg to about 50 mg / kg, from about 10 μg / kg to about 10 mg / kg, from about 50 μg / kg to about 1 mg / kg, or from about 100 μg / kg to about 500 μg / kg.

[0546] Methods of targeted delivery and methods of knocking down target molecules to a target In another aspect, Formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A method for targeted delivery of a compound comprising the structure of formula 20 to a specific tissue, organ or cell in a subject in need of targeted delivery of the compound to a specific tissue, organ or cell, (i) covalently linking a ligand molecule or a functional analog thereof for a glucose transporter (GLUT) via a second linker or bond to the A terminus, B terminus or a combination thereof of a compound comprising the structure of formula 20, (ii) administering to the subject comprising, wherein the specific tissue, organ or cell expresses GLUT, and the compound is delivered to the specific tissue, organ or cell to a greater extent than to tissues, organs or cells that do not express GLUT, is provided herein.

[0547] In another aspect, a compound for targeted delivery to a specific tissue, organ or cell in a subject in need of targeted delivery to a specific tissue, organ or cell, the compound having the formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) comprising the structure of, wherein a ligand molecule or a functional analog thereof for a glucose transporter (GLUT) is covalently linked via a second linker or bond to the A terminus, B terminus or a combination thereof, wherein the specific tissue, organ or cell expresses GLUT, and when administered to the subject, the compound is delivered to the specific tissue, organ or cell to a greater extent than to tissues, organs or cells that do not express GLUT, is provided herein.

[0548] In some embodiments, the compound is delivered to a particular tissue, organ, or cell that expresses GLUT to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 800%, about 850%, about 900%, about 1000%, about 1500%, about 2000%, about 2500%, about 3000%, about 3500%, about 4000%, about 4500%, about 5000%, about 5500%, about 6000%, about 6500%, about 7000%, about 7500%, about 8000%, about 8500%, about 9000%, about 9500%, about 10000%, about 15000%, about 20000%, about 25000%, about 30000%, about 35000%, about 40000%, about 45000%, about 50000%, about 55000%, about 60000%, about 65000%, about 70000%, about 75000%, about 80000%, about 85000%, about 90000%, about 100000% or more, compared to a tissue, organ, or cell that does not express GLUT.In some embodiments, the compound is delivered to a particular tissue, organ, or cell that expresses GLUT to a greater extent, by at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1000-fold, about 1500-fold, about 2000-fold, about 2500-fold, about 3000-fold, about 3500-fold, about 4000-fold, about 4500-fold, about 5000-fold, about 5500-fold, about 6000-fold, about 6500-fold, about 7000-fold, about 7500-fold, about 8000-fold, about 8500-fold, about 9000-fold, about 9500-fold, about 10000-fold (10000 - folds - folds), about 20000-fold, about 30000-fold, about 40000-fold, about 50000-fold, 60000-fold, about 70000-fold, about 80000-fold, about 90000-fold, about 100000-fold or more, compared to a tissue, organ, or cell that does not express GLUT.

[0549] In some embodiments, R is an inhibitory oligonucleotide molecule.

[0550] In another aspect, a method of reducing or inhibiting the expression and / or activity of a target molecule in a particular tissue, organ, or cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula 17: A - X - R - Y - B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) comprising administering a compound having the structure of Formula 17. A ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the end of A, the end of B, or a combination thereof, a specific tissue, organ or cell expresses GLUT, The present specification provides a method in which a compound reduces or inhibits the expression and / or activity of a target molecule in a specific tissue, organ or cell to a greater extent compared to the expression and / or activity of the target molecule in a tissue, organ or cell that does not express GLUT.

[0551] In another aspect, a compound for reducing or inhibiting the expression and / or activity of a target molecule in a specific tissue, organ or cell in a subject in need thereof, having the structure of Formula 17: A-X-R-Y-B Formula 17 (wherein, R is an inhibitory oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) comprising the structure of, a ligand molecule for a glucose transporter (GLUT) or a functional analog thereof is covalently linked via a second linker or bond to the end of A, the end of B, or a combination thereof, a specific tissue, organ or cell expresses GLUT, The present specification provides a compound in which a compound reduces or inhibits the expression and / or activity of a target molecule in a specific tissue, organ or cell to a greater extent compared to the expression and / or activity of the target molecule in a tissue, organ or cell that does not express GLUT.

[0552] In some embodiments, the compound reduces or inhibits the expression of a target molecule in a particular tissue, organ, or cell to a greater extent compared to the expression of the target molecule in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound reduces or inhibits the expression of the target molecule in a particular tissue, organ, or cell to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to the expression of the target molecule in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound reduces or inhibits the activity of a target molecule in a particular tissue, organ, or cell to a greater extent compared to the activity of the target molecule in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound reduces or inhibits the activity of the target molecule in a particular tissue, organ, or cell to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to the activity of the target molecule in a tissue, organ, or cell that does not express GLUT.

[0553] The compound regulates the expression and / or activity of a target molecule in a specific tissue, organ, or cell to a greater extent compared to the expression and / or activity of the target molecule in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound regulates the expression of the target molecule in a specific tissue, organ, or cell to a greater extent compared to the target molecule expression in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound regulates the expression of the target molecule in a specific tissue, organ, or cell to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to the target molecule expression in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound regulates the activity of the target molecule in a specific tissue, organ, or cell to a greater extent compared to the target molecule activity in a tissue, organ, or cell that does not express GLUT. In some embodiments, the compound regulates the activity of the target molecule in a specific tissue, organ, or cell to a greater extent, by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%, compared to the target molecule activity in a tissue, organ, or cell that does not express GLUT.

[0554] In some embodiments, the second linker is -NH(CH2)nCONH-CH2-CH(OH)-CH2-, an ether bond, or Compound 4:

Chemical formula

Chemical formula

[0555] In some embodiments, the second linker is any one listed in Table 7.

[0556] In some embodiments, the specific tissues, organs, or cells that express GLUT include the brain, blood, brain, intestine, liver, kidney, pancreas, embryo, testis, placenta, muscle, heart, fat, adipose tissue, spleen, colon, prostate, testis, blastocyst, skeletal muscle, white adipose tissue, brown adipose tissue, or any combination thereof.

[0557] In some embodiments, (i) GLUT is GLUT1, and the specific tissues, organs, or cells that express GLUT include the brain, blood, or a combination thereof; (ii) GLUT is GLUT2, and the specific tissues, organs, or cells that express GLUT include the brain, intestine, liver, kidney, pancreas, or any combination thereof; (iii) GLUT is GLUT3, and the specific tissues, organs, or cells that express GLUT include the brain, embryo, testis, placenta, or any combination thereof; (iv) GLUT is GLUT4, and the specific tissues, organs, or cells that express GLUT include the brain, muscle, heart, fat, adipose tissue, or any combination thereof; (v) GLUT is GLUT5, and the specific tissues, organs, or cells that express GLUT include the brain, intestine, testis, muscle, kidney, fat, or any combination thereof; (vi) GLUT is GLUT6, and the specific tissues, organs, or cells that express GLUT include the brain, spleen, or a combination thereof; (vii) GLUT is GLUT7, and the specific tissues, organs, or cells that express GLUT include the intestine, colon, prostate, testis, prostate, or any combination thereof; (viii) The GLUT is GLUT8, and the specific tissues, organs, or cells expressing GLUT include the brain, testis, liver, spleen, adipose tissue, blastocyst, or any combination thereof; (ix) The GLUT is GLUT9, and the specific tissues, organs, or cells expressing GLUT include the liver, kidney, intestine, colon, or any combination thereof; (x) The GLUT is GLUT10, and the specific tissues, organs, or cells expressing GLUT include the liver, pancreas, adipose tissue, skeletal muscle, heart, adipose tissue, placenta, kidney, or any combination thereof; (xi) The GLUT is GLUT11, and the specific tissues, organs, or cells expressing GLUT include the heart, muscle, kidney, pancreas, placenta, or any combination thereof; (xii) The GLUT is GLUT12, and the specific tissues, organs, or cells expressing GLUT include the brain, muscle, heart, adipose tissue, pancreas, prostate gland, adipose tissue, placenta, kidney, or any combination thereof; (xiii) The GLUT is GLUT13, and the specific tissues, organs, or cells expressing GLUT include the brain, white adipose tissue, brown adipose tissue, kidney, or any combination thereof; or (xiv) The GLUT is GLUT14, and the specific tissues, organs, or cells expressing GLUT include the testis.

[0558] In some embodiments, (i) the GLUT is GLUT1, and the specific tissues, organs, or cells expressing GLUT include the blood-brain barrier, astrocytes, erythrocytes, or any combination thereof; (ii) the GLUT is GLUT2, and the specific tissues, organs, or cells expressing GLUT include astrocytes, gastrointestinal tract, small intestine, intestinal absorptive epithelial cells, hepatocytes, pancreatic β cells, brain nuclei, solitary tract nucleus, vagus nerve motor nucleus, paraventricular hypothalamic nucleus, lateral hypothalamic area, arcuate nucleus, and olfactory bulb, or any combination thereof; (iii) The GLUT is GLUT3, and the specific tissues, organs, or cells expressing GLUT include neurons, blood-brain barrier, astrocytes, sperm (spermatozoa), fibroblasts, platelets, retinal endothelial cells, leukocytes, or any combination thereof; (iv) The GLUT is GLUT4, and the specific tissues, organs, or cells expressing GLUT include neurons, adipocytes, skeletal muscle cells, cardiomyocytes, hypothalamus, cerebellum, cortex, and hippocampus, or combinations thereof; (v) The GLUT is GLUT5, and the specific tissues, organs, or cells expressing GLUT include microglia, blood-brain barrier, small intestine, apical membrane of intestinal cells, plasma membrane of mature sperm, skeletal muscle, or any combination thereof; (vi) The GLUT is GLUT6, and the specific tissues, organs, or cells expressing GLUT include leukocytes, peripheral leukocytes, germ cells of testis, or any combination thereof; (vii) The GLUT is GLUT7, and the specific tissues, organs, or cells expressing GLUT include the small intestine; (viii) The GLUT is GLUT8, and the specific tissues, organs, or cells expressing GLUT include neurons, brown adipose tissue, cerebellum, adrenal gland, spermatocytes, mature sperm, or any combination thereof; (ix) The GLUT is GLUT9, and the specific tissues, organs, or cells expressing GLUT include the small intestine, leukocytes, chondrocytes, or any combination thereof; (x) The GLUT is GLUT10, and the specific tissues, organs, or cells expressing GLUT include white fat; (xi) The GLUT is GLUT12, and the specific tissues, organs, or cells expressing GLUT include astrocytes, prostate, small intestine, chondrocytes, or any combination thereof; or (xii) The GLUT is GLUT13, and the specific tissues, organs, or cells expressing GLUT include neurons.

[0559] In some embodiments, the specific tissues, organs or cells that express GLUT include cancer cells.

[0560] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, glioblastoma, pancreatic cancer, leukemia, gastric cancer, colorectal cancer, and any combination thereof.

[0561] In some embodiments, (i) GLUT is GLUT1, and the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, skin cancer, thyroid cancer, and any combination thereof; (ii) GLUT is GLUT3, and the cancer is selected from the group consisting of brain cancer, breast cancer, colon cancer, cervical cancer, kidney cancer, lung cancer, glioblastoma and any combination thereof; (iii) GLUT is GLUT5, and the cancer is selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, leukemia, and any combination thereof; (iv) GLUT is GLUT10, and the cancer is leukemia; (v) GLUT is GLUT12, and the cancer is breast cancer; or (vi) GLUT is GLUT14, and the cancer is brain cancer.

[0562] In some embodiments, the specific tissues, organs, or cells that express GLUT include any one of the tissues, organs, or cells listed in Table 4 or Table 5, or any combination thereof.

[0563] Method for improving blood-brain barrier permeability In another aspect, Formula 20: A-X-R-Y-B Formula 20 (wherein, R is an oligonucleotide molecule, A is a hydrophilic moiety, B is a hydrophobic moiety, X and Y are independently a covalent bond or a first linker) A method for increasing the blood-brain barrier permeability of a compound having the structure of Formula 20 in a subject in need of an increase in the blood-brain barrier permeability of a compoun...

Claims

1. A double-stranded oligonucleotide structure comprising the structure of the following formula 1. AX-RY-B (Formula 1) (R is a double-stranded oligonucleotide comprising a sense strand and an antisense strand containing a complementary sequence.) X and Y are independently covalent or linkers.) A is the hydrophilic part, and B is the hydrophobic part, The ligand molecule or its functional analogue for the glucose transporter (GLUT) is covalently linked to the A and / or B terminals via a second linker.

2. The structure of formula 1 is, Formula 14 or Formula 15 below: (L i )-AX-RY-B (Formula 14) (L is a ligand molecule for glucose transporter (GLUT), or a functional analog thereof, and i is an integer between 1 and 10. AX-RY-B-(L j ) (Formula 15) (L is a ligand molecule for glucose transporter (GLUT), or a functional analog thereof, and j is an integer between 1 and 10. A double-stranded oligonucleotide structure according to claim 1, represented by [formula].

3. The double-stranded oligonucleotide structure according to claim 2, wherein L is a sugar.

4. The double-stranded oligonucleotide structure according to claim 3, wherein L is a monosaccharide.

5. The double-stranded oligonucleotide structure according to claim 3, wherein the sugar is selected from the group consisting of fructose, galactose, glucosamine, glucose, mannose, xylose, dehydroascorbic acid, and trehalose.

6. The double-stranded oligonucleotide structure according to claim 1, wherein the glucose transporter (GLUT) is selected from the group consisting of GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14.

7. The double-stranded oligonucleotide structure according to claim 1, wherein A is a hydrophilic portion selected from the group consisting of polyethylene glycol (PEG), hexaethylene glycol (HEG), polyvinylpyrrolidone, and polyoxazoline.

8. The double-stranded oligonucleotide structure according to claim 1, wherein B comprises a hydrophobic moiety having a molecular weight of 250 to 1,000.

9. The double-stranded oligonucleotide structure according to claim 1, wherein B comprises a hydrophobic moiety selected from the group consisting of steroid derivatives, glyceride derivatives, glycerol ethers, polypropylene glycol, unsaturated or saturated C12 to C50 hydrocarbon chains, diacylphosphatidylcholine, fatty acids, phospholipids, lipopolyamines, lipids, tocopherols, and tocotrienols.

10. The double-stranded oligonucleotide structure according to claim 9, wherein B comprises a hydrophobic moiety selected from the group consisting of glyceride derivatives, glycerol ethers, unsaturated or saturated C12 to C50 hydrocarbon chains, and lipopolyamines, and optionally B is C6-S-S-C18.

11. The double-stranded oligonucleotide structure according to claim 1, wherein A is represented by the following formula. (A' m - J) n or (J-A' m) n (In the formula, A' is a hydrophilic portion selected from compound 1, compound 2, or compound 3.) Compound 1, 【Chemistry 1】 (In the formula, G is selected from O, S, and NH.) Compound 2, 【Chemistry 2】 or Compound 3 【Transformation 3】 J is selected from PO3-, SO3-, or ester. m is an integer from 1 to 15, and n is an integer between 1 and 10.

12. The double-stranded oligonucleotide structure according to claim 11, wherein G is O and J is PO3-.

13. The double-stranded oligonucleotide structure according to claim 12, wherein m is 5 to 10 and n is 2 to 7.

14. The linker is an ether bond, hexaethylene glycol, -NH(CH2)nCONH-CH2-CH(OH)-CH2-, -N(COCH3)(CH2)nCONH-CH2-CH(OH)-CH2- (where n is an integer from 1 to 10), or compound 4: Compound 4, 【Chemistry 4】 (In the formula, T is one of the repeating compounds 1 to 15: Compound 1 【Transformation 5】 (where G is selected from CH₂, O, S, and NH) The double-stranded oligonucleotide structure according to claim 1.

15. The double-stranded oligonucleotide structure according to claim 14, wherein n is 5 and G is O.

16. The double-stranded oligonucleotide structure according to claim 1, wherein the double-stranded oligonucleotide comprises a sequence that targets hu-BACE1 or hu-MAPT.

17. The double-stranded oligonucleotide structure according to claim 16, wherein the double-stranded oligonucleotide comprises a sequence targeting hu-BACE1, and the sequence is selected from SEQ ID NOs. 22 to 45.

18. The double-stranded oligonucleotide structure according to claim 16, wherein the double-stranded oligonucleotide comprises a sequence that targets hu-MAPT, and optionally the sequence is selected from SEQ ID NOs: 46 to 68.

19. The double-stranded oligonucleotide structure according to claim 1, wherein the double-stranded oligonucleotide comprises a sequence selected from sequence numbers 22 to 131.

20. A nanoparticle comprising a double-stranded oligonucleotide structure according to any one of claims 1 to 19.

21. A pharmaceutical composition comprising the nanoparticles described in Claim 20.

22. A pharmaceutical composition comprising a double-stranded oligonucleotide structure according to any one of claims 1 to 19.

23. The pharmaceutical composition according to claim 22 for use in the treatment of neurological disorders.

24. The pharmaceutical composition according to claim 23 for use, wherein the neurological disorder is Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury.

25. The pharmaceutical composition according to claim 21 for use in the treatment of neurological disorders.

26. The pharmaceutical composition according to claim 25 for use, wherein the neurological disorder is Alzheimer's disease (AD), stroke, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, or traumatic brain injury.

27. ​​A kit comprising a double-stranded oligonucleotide structure according to any one of claims 1 to 19.

Images