Compounds and methods for reducing ifnar1 expression

Abstract

Provided are oligomeric compounds, methods, and pharmaceutical compositions for reducing the amount or activity of IFNAR1 RNA in a cell or animal, and in certain instances reducing the amount of IFNAR1 protein in a cell or animal. Such oligomeric compounds, methods, and pharmaceutical compositions are useful to treat diseases and conditions associated with neuroinflammation, including Aicardi-Goutières Syndrome, stroke, neuropsychiatric systemic lupus erythematosus, neuroinflammation following traumatic brain injury, neuro-autoimmune disorders, Alzheimer's disease, post-operative delirium and cognitive decline, cranial radiation-induced cognitive decline, viral infection-induced cognitive decline, neuromyelitis optica, and ataxia telangiectasia.

1 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         2 . The modified oligonucleotide of  claim 1 , which is the sodium salt or the potassium salt. 
     
     
         3 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         5 . The modified oligonucleotide of  claim 4 , which is the sodium salt or the potassium salt. 
     
     
         6 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         8 . The modified oligonucleotide of  claim 7 , which is the sodium salt or the potassium salt. 
     
     
         9 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         11 . The modified oligonucleotide of  claim 10 , which is the sodium salt or the potassium salt. 
     
     
         12 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         14 . The modified oligonucleotide of  claim 13 , which is the sodium salt or the potassium salt. 
     
     
         15 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         17 . The modified oligonucleotide of  claim 16 , which is the sodium salt or the potassium salt. 
     
     
         18 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         19 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: T es   m C eo G eo   m C eo   m C es T ds A ds A ds T ds T ds T ds T ds T ds   m C ds T ds   m C eo T eo   m C es A es   m C e  (SEQ ID NO 19), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         20 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:  m C es T eo T eo T eo T eo T em C ds T ds G ds   m C ds T ds   m C ds T ds T ds A ds T ds A eo   m C es G es   m Ce (SEQ ID NO 16), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         21 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:  m C es T eo G eo T eo T eo T eo T ds A ds   m C ds A ds T ds T ds T ds T ds T ds T ds T eo T es   m C es   m C e  (SEQ ID NO 17), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         22 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: T es T eo T eo A eo T es   m C ds   m C ds A ds A ds T ds T ds A ds T ds   m C ds   m C ds A eo T eo   m C es   m C es   m C e  (SEQ ID NO 18), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         23 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: T es T eo T eo   m C eo A eo T eo A ds T ds T ds T ds G ds T ds T ds A ds   m C ds T ds T eo   m C es   m C es T e  (SEQ ID NO 20), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         24 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: T es T eo   m C eo G eo   m C eo   m C eo T ds A ds A ds T ds T ds T ds T ds T ds   m C ds T ds   m C eo T es   m C es A e  (SEQ ID NO 21), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   e=a 2′-MOE sugar moiety,   d=a 2′-β-D-deoxyribosyl sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         25 . A population of modified oligonucleotides of any of  claims 1 - 18  or a population of oligomeric compounds of any of  claims 19 - 24 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         26 . A pharmaceutical composition comprising a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , or a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , and a pharmaceutically acceptable diluent. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide, the oligomeric compound, or the population, and artificial cerebrospinal fluid or phosphate-buffered saline. 
     
     
         29 . A method comprising administering to a subject a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , or a pharmaceutical composition of any of  claims 26 - 28 . 
     
     
         30 . A method of treating a disease associated with type I interferon signaling, comprising administering to a subject having a disease associated with type I interferon signaling a therapeutically effective amount of a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , or a pharmaceutical composition of any of  claims 26 - 28 ; thereby treating the disease associated with type I interferon signaling. 
     
     
         31 . The method of  claim 30 , wherein the disease associated with type I interferon signaling is Aicardi-Goutières Syndrome, stroke, Neuropsychiatric Systemic Lupus Erythematosus, neuroinflammation following traumatic brain injury, neuro-autoimmune disorders, Alzheimer's disease, post-operative delirium and cognitive decline, cranial radiation-induced cognitive decline, viral infection-induced cognitive decline, neuromyelitis optica, or ataxia telangiectasia. 
     
     
         32 . The method of  claim 30  or  claim 31 , wherein the disease is associated with an elevated level of interferon-alpha. 
     
     
         33 . The method of any of  claims 30 - 32 , wherein administering the modified oligonucleotide, the oligomeric compound, the population of modified oligonucleotides or population of oligomeric compounds, or the pharmaceutical composition reduces seizures, dystonia, spasticity, white matter abnormalities, T cell infiltration, B cell infiltration, striatal necrosis, brain atrophy, basal ganglia calcification, or microencephaly in the subject; improves feeding, motor development, language development, or social skill development in the subject; or reduces interferon alpha or lymphocytosis in the cerebrospinal fluid of the subject. 
     
     
         34 . A method of reducing expression of IFNAR1 in a cell, comprising contacting the cell with a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , or a pharmaceutical composition of any of  claims 26 - 28 . 
     
     
         35 . The method of  claim 34 , wherein the cell is a neuron or a glial cell, optionally wherein the cell is an astrocyte or microglial cell. 
     
     
         36 . The method of any of  claims 29 - 33 , wherein the subject is human. 
     
     
         37 . The method of  claim 34  or  claim 35 , wherein the cell is a human cell. 
     
     
         38 . Use of a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , or a pharmaceutical composition of any of  claims 26 - 28  for treating a disease associated with type I interferon signaling. 
     
     
         39 . Use of a modified oligonucleotide of any of  claims 1 - 18 , an oligomeric compound of any of  claims 19 - 24 , a population of modified oligonucleotides or population of oligomeric compounds of  claim 25 , or a pharmaceutical composition of any of  claims 26 - 28  in the manufacture of a medicament for treating a disease associated with type I interferon signaling. 
     
     
         40 . The use of  claim 38  or  claim 39 , wherein the disease is associated with an elevated level of interferon alpha. 
     
     
         41 . The use of any of  claims 38 - 40 , wherein the disease associated with type I interferon signaling is Aicardi-Goutières Syndrome, stroke, neuropsychiatric systemic lupus erythematosus, neuroinflammation following traumatic brain injury, neuro-autoimmune disorders, Alzheimer's disease, post-operative delirium and cognitive decline, cranial radiation-induced cognitive decline, viral infection-induced cognitive decline, neuromyelitis optica, or ataxia telangiectasia.