US2017369882A1PendingUtilityA1

Fully stabilized asymmetric sirna

58
Assignee: UNIV MASSACHUSETTSPriority: Apr 3, 2015Filed: Aug 30, 2017Published: Dec 28, 2017
Est. expiryApr 3, 2035(~8.7 yrs left)· nominal 20-yr term from priority
Inventors:Anastasia KhvorovaNeil AroninMatthew HasslerJulia Alterman
A61P 43/00A61P 25/14C12N 15/1138C12N 15/111C12N 2320/53C12N 2320/51A61P 1/16C12N 2310/346C12Y 207/10001C12N 2310/315C12N 2310/344C12N 15/113C12N 2310/14C12N 2310/3515A61P 15/00C12N 2310/321A61P 13/12C12N 2310/343
58
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Claims

Abstract

Provided herein are self-delivering oligonucleotides that are characterized by efficient RISC entry, minimum immune response and off-target effects, efficient cellular uptake without formulation, and efficient and specific tissue distribution.

Claims

exact text as granted — not AI-modified
1 . A method of treating or managing Huntington's disease, comprising administering to a patient in need of such treatment or management a therapeutically effective amount of a vector comprising a regulatory sequence operatively linked to a nucleotide sequence encoding a double-stranded RNA substantially complementary to 5′ AGUACUUCAACGCUA 3′ (SEQ ID NO: 621), wherein the dsRNA molecule targets an HTT mRNA. 
     
     
         2 . The method of  claim 1 , wherein said vector comprises a lentiviral vector or Adeno-Associated Virus (AAV) vector. 
     
     
         3 . The method of  claim 1 , wherein said vector is administered to the brain of the patient. 
     
     
         4 . The method of  claim 1 , wherein said vector is administered by intrastriatal injection. 
     
     
         5 . The method of  claim 1 , wherein the dsRNA causes a decrease in HTT gene mRNA in the striatum. 
     
     
         6 . The method of  claim 1 , wherein each strand of the dsRNA is between 10 and 50 base pairs in length. 
     
     
         7 . The method of  claim 1 , wherein each strand of the dsRNA is between 16 and 30 base pairs in length. 
     
     
         8 . The method of  claim 1 , wherein the dsRNA blunt-ended. 
     
     
         9 . The method of  claim 1 , wherein the dsRNA comprises at least one single stranded nucleotide overhang. 
     
     
         10 . The method of  claim 1 , wherein the dsRNA comprises at least one mismatched nucleotide. 
     
     
         11 . The vector of  claim 1 , wherein the dsRNA contains at least one internal bulge. 
     
     
         12 . A pharmaceutical composition comprising a vector comprising a regulatory sequence operatively linked to a nucleotide sequence encoding a double-stranded RNA substantially complementary to 5′ AGUACUUCAACGCUA 3′ (SEQ ID NO: 621), wherein the dsRNA inhibits the expression of Htt mRNA, wherein the pharmaceutical composition is administered at a therapeutically effective amount to a patient having Huntington's Disease. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said vector comprises a lentiviral vector or Adeno-Associated Virus (AAV) vector. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the dsRNA contains at least one internal bulge. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein each strand of the dsRNA is between 16 and 30 base pairs in length. 
     
     
         16 . A method of treating or managing Huntington's disease, comprising administering to a patient in need of such treatment or management a therapeutically effective amount of a vector comprising a regulatory sequence operatively linked to a nucleotide sequence encoding a double-stranded RNA substantially complementary to 5′ CUAGCUCCAUGCUUA 3′ (SEQ ID NO:623), wherein the dsRNA molecule targets an HTT mRNA. 
     
     
         17 . The method of  claim 16 , wherein said vector comprises a lentiviral vector or Adeno-Associated Virus (AAV) vector. 
     
     
         18 . The method of  claim 16 , wherein said vector is administered to the brain of the patient. 
     
     
         19 . The method of  claim 16 , wherein said vector is administered by intrastriatal injection. 
     
     
         20 . The method of  claim 16 , wherein the dsRNA causes a decrease in HTT gene mRNA in the striatum. 
     
     
         21 . The method of  claim 16 , wherein each strand of the dsRNA is between 10 and 50 base pairs in length. 
     
     
         22 . The method of  claim 16 , wherein each strand of the dsRNA is between 16 and 30 base pairs in length. 
     
     
         23 . The method of  claim 16 , wherein the dsRNA blunt-ended. 
     
     
         24 . The method of  claim 16 , wherein the dsRNA comprises at least one single stranded nucleotide overhang. 
     
     
         25 . The method of  claim 16 , wherein the dsRNA comprises at least one mismatched nucleotide. 
     
     
         26 . The vector of  claim 16 , wherein the dsRNA contains at least one internal bulge. 
     
     
         27 . A pharmaceutical composition, comprising a vector comprising a regulatory sequence operatively linked to a nucleotide sequence encoding a double-stranded RNA substantially complementary to 5′ CUAGCUCCAUGCUUA 3′ (SEQ ID NO: 623), wherein the dsRNA inhibits the expression of Htt mRNA, wherein the pharmaceutical composition is administered at a therapeutically effective amount to a patient having Huntington's Disease. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said vector comprises a lentiviral vector or Adeno-Associated Virus (AAV) vector. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the dsRNA contains at least one internal bulge. 
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein each strand of the dsRNA is between 16 and 30 base pairs in length.

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