US2019022019A1PendingUtilityA1

POLYNUCLEOTIDES ENCODING METHYLMALONYL-CoA MUTASE

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Assignee: MODERNATX INCPriority: Dec 17, 2015Filed: Aug 27, 2018Published: Jan 24, 2019
Est. expiryDec 17, 2035(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:Paolo MartiniVladimir Presnyak
A61K 9/1272C12Y 504/99002C12N 15/52A61P 43/00A61P 3/00A61K 9/5123C12N 9/90A61K 38/52A61K 38/00A61K 48/005C12N 15/88
72
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Claims

Abstract

The disclosure relates to polynucleotides comprising an open reading frame of linked nucleosides encoding human methylmalonyl-CoA mutase precursor, human methylmalonyl-CoA mutase (MCM) mature form, or functional fragments thereof. In some embodiments, the disclosure includes methods of treating methylmalonic acidemia in a subject in need thereof comprising administering an mRNA encoding an MCM polypeptide.

Claims

exact text as granted — not AI-modified
1 - 15 . (canceled) 
     
     
         16 . A messenger RNA (mRNA) comprising:
 (i) a 5′-terminal cap;   (ii) a 5′ untranslated region (UTR);   (iii) an open reading frame (ORF) encoding the human methylmalonyl-CoA mutase (MCM) polypeptide of SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, or SEQ ID NO:213, wherein at least 95% of uracils in the ORF are 5-methoxyuracils, and wherein the uracil content in the ORF is below 150% of the theoretical minimum;   (iv) a 3′ UTR; and   (v) a poly-A tail.   
     
     
         17 . The mRNA of  claim 16 , wherein the uracil content in the ORF is above 100% of the theoretical minimum. 
     
     
         18 . The mRNA of  claim 16 , wherein the uracil content in the ORF is between 123% and 125%, between 122% and 126%, between 121% and 127%, between 120% and 128%, between 119% and 129%, between 118% and 130%, between 117% and 131%, between 116% and 132%, between 115% and 133%, between 114% and 134%, between 113% and 135%, between 112% and 136%, or between 111% and 137% of the theoretical minimum. 
     
     
         19 . The mRNA of  claim 16 , wherein the uracil content in the ORF is between 118% and 129% of the theoretical minimum. 
     
     
         20 . The mRNA of  claim 16 , wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:213. 
     
     
         21 . The mRNA of  claim 20 , wherein the ORF is at least 80% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         22 . The mRNA of  claim 20 , wherein the ORF is at least 85% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         23 . The mRNA of  claim 20 , wherein the ORF is at least 90% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         24 . The mRNA of  claim 20 , wherein the ORF is at least 95% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         25 . The mRNA of  claim 20 , wherein the ORF is at least 98% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         26 . The mRNA of  claim 20 , wherein the ORF is at least 99% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         27 . The mRNA of  claim 20 , wherein the ORF is 100% identical to the nucleotide sequence of SEQ ID NO:732. 
     
     
         28 . The mRNA of  claim 21 , wherein the 5′ UTR comprises the nucleotide sequence of SEQ ID NO:215. 
     
     
         29 . The mRNA of  claim 21 , wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO:722. 
     
     
         30 . The mRNA of  claim 21 , wherein the 5′ terminal cap is Cap1. 
     
     
         31 . The mRNA of  claim 21 , wherein the poly-A tail is 100 residues in length. 
     
     
         32 . The mRNA of  claim 27 , wherein the 5′ UTR comprises the nucleotide sequence of SEQ ID NO:215. 
     
     
         33 . The mRNA of  claim 27 , wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO:722. 
     
     
         34 . The mRNA of  claim 27 , wherein the 5′ terminal cap is Cap1. 
     
     
         35 . The mRNA of  claim 27 , wherein the poly-A tail is 100 residues in length. 
     
     
         36 . The mRNA of  claim 27 , wherein the 5′ UTR comprises the nucleotide sequence of SEQ ID NO:215, wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO:722, wherein the 5′ terminal cap is Cap1, and wherein the poly-A tail is 100 residues in length. 
     
     
         37 . A pharmaceutical composition comprising the mRNA of  claim 16  and a pharmaceutically acceptable excipient. 
     
     
         38 . A pharmaceutical composition comprising the mRNA of  claim 27  and a pharmaceutically acceptable excipient. 
     
     
         39 . A pharmaceutical composition comprising the mRNA of  claim 36  and a pharmaceutically acceptable excipient. 
     
     
         40 . A lipid nanoparticle comprising the mRNA of  claim 16 . 
     
     
         41 . A lipid nanoparticle comprising the mRNA of  claim 27 . 
     
     
         42 . A lipid nanoparticle comprising the mRNA of  claim 36 . 
     
     
         43 . A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the pharmaceutical composition of  claim 37 . 
     
     
         44 . A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the pharmaceutical composition of  claim 38 . 
     
     
         45 . A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the pharmaceutical composition of  claim 39 .

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