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