Treatment of primary ciliary dyskinesia with synthetic messenger rna

Abstract

Polynucleotides encoding peptides, proteins, enzymes, and functional fragments thereof are disclosed. The polynucleotides of the disclosure can be effectively delivered to an organ, such as the lung, and expressed within cells of the organ. The polyribonucleotides of the disclosure can be used to treat a disease or condition associated with cilia maintenance and function, impaired function of the axoneme, such as DNAI1 or DNAH5.

what is claimed is: 
     
         1 . A pharmaceutical formulation comprising a polynucleotide that is at least 70% homologous to nucleic acids 1-1,000 of SEQ ID NO: 15, which composition is formulated for administration to a subject. 
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein said polynucleotide is at least 80% homologous to nucleic acids 1-1,000 of SEQ ID NO: 15. 
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein said polynucleotide is an mRNA. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein fewer than 15% of nucleotides within said polynucleotide are nucleotide analogues. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein substantially all nucleotides replacing uracil within said polynucleotide are nucleotide analogues. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein said polynucleotide comprises 1-methylpseudouridine. 
     
     
         7 . The pharmaceutical formulation of  claim 1 , wherein said pharmaceutical formulation comprises a cationic lipid, a fusogenic lipid, a cholesterol and a polyethylene glycol (PEG) lipid. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein said composition is formulated using a cationic lipid or a cationic polymer. 
     
     
         9 . The pharmaceutical formulation of  claim 11 , wherein said formulation includes a therapeutically effective amount of said polynucleotide. 
     
     
         10 . The pharmaceutical formulation of  claim 1 , wherein said composition is formulated in a nanoparticle or nanocapsule. 
     
     
         11 . The pharmaceutical formulation of  claim 1 , wherein said polynucleotide further comprises a 3′ or 5′ noncoding region, wherein said 3′ or 5′ noncoding region enhances the expression of said dynein axonemal intermediate chain 1 polypeptide within cells of said subject. 
     
     
         12 . The pharmaceutical formulation of  claim 11 , wherein said polynucleotide further comprises a 5′ cap structure. 
     
     
         13 . The pharmaceutical formulation of  claim 11 , wherein said 3′ noncoding region comprises a poly adenosine tail. 
     
     
         14 . The pharmaceutical formulation of  claim 13 , wherein said poly adenosine tail improves the half-life of said dynein axonemal intermediate chain 1 polypeptide. 
     
     
         15 . The pharmaceutical formulation of  claim 13 , wherein a length of said poly adenosine tail is at most 200 adenosines. 
     
     
         16 . A vector comprising said polynucleotide of  claim 1 . 
     
     
         17 . An isolated nucleic acid comprising said polynucleotide of  claim 1  and a heterologous sequence. 
     
     
         18 . A method for treating primary ciliary dyskinesia comprising administrating to a subject a pharmaceutical formulation of  claim 1 . 
     
     
         19 . A pharmaceutical formulation comprising:
 a) a nucleic acid construct that is at least 70% homologous to a dynein axonemal intermediate chain 1 polypeptide, which nucleic acid construct includes codons that provide for heterologous or enhanced expression of the dynein axonemal intermediate chain 1 protein within cells of a subject having or at risk of having primary ciliary dyskinesia; and   b) a cationic lipid, a fusogenic lipid, a cholesterol and a polyethylene glycol (PEG) lipid.   
     
     
         20 . The pharmaceutical formulation of  claim 19 , wherein fewer than 15% of nucleotides within said nucleic acid construct are nucleotide analogues.