TREATMENT OF CYSTIC FIBROSIS BY DELIVERY OF NEBULIZED mRNA ENCODING CFTR

Abstract

The present invention provides, among other things, an improved method of treating cystic fibrosis (CF) in a human subject. The method comprises administering a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein at a concentration of 0.5 mg/mL or greater to a human subject via nebulization. The composition is aerosolized using a nebulizer and a nominal dose of the mRNA is administered to the human subject via the nebulizer over a period of time, typically at least 30 minutes, at a suitable nebulization rate, e.g., at least 0.2 mL/minute.

1 . A method of treating cystic fibrosis (CF) in a human subject comprising administering a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein at a concentration of 0.5 mg/mL or greater to the human subject, wherein the step of administering comprises the following: (i) the composition is aerosolized using a nebulizer, and (ii) a nominal dose of the mRNA is administered to the human subject via the nebulizer over a period of time at least 30 minutes at a nebulization rate of at least 0.2 mL/minute. 
     
     
         2 . The method of  claim 1 , wherein the concentration of the mRNA encoding the CFTR protein ranges from 0.5 mg/mL to 0.8 mg/mL, optionally wherein the concentration is 0.6 mg/mL. 
     
     
         3 . The method of  claim 1 , wherein at least 25%, at least 35%, or at least 40% of the nominal dose is delivered to the lungs of the human subject. 
     
     
         4 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the nebulization rate ranges from 0.2 mL/minute to 0.5 mL/minute. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the median droplet size in the aerosolized composition is between 4 and 6 μm. 
     
     
         12 . The method of  claim 1 , wherein at least a portion of the mRNA encoding the CFTR protein is complexed to or encapsulated within nanoparticles. 
     
     
         13 . The method of  claim 12 , wherein the nanoparticles are liposomes and at least 80% of the mRNA encoding the CFTR protein is encapsulated within the liposome. 
     
     
         14 . The method of  claim 13 , wherein the liposome has a size of less than about 100 nm. 
     
     
         15 . The method of  claim 14 , wherein the liposome has a size ranging from 40 nm to 60 nm. 
     
     
         16 . The method of  claim 11 , wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, and one or more PEG-modified lipids. 
     
     
         17 . The method of  claim 16 , wherein the liposome comprises no more than three distinct lipid components. 
     
     
         18 . The method of  claim 17 , wherein one distinct lipid component is a sterol-based cationic lipid. 
     
     
         19 - 23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein the mRNA has poly-A tail with an average length of at least 100 bases. 
     
     
         25 - 32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the composition is provided in lyophilized form and reconstituted in an aqueous solution prior to nebulization. 
     
     
         34 . The method of  claim 1 , wherein the composition comprises trehalose. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein the human subject is administered the composition at least once per week for a period of at least six months. 
     
     
         37 . The method of  claim 1 , wherein the human subject receives concomitant CFTR modulator therapy. 
     
     
         38 . The method of  claim 37 , wherein the concomitant CFTR modulator therapy is selected from ivacaftor, ivacaftor/lumacaftor, or tezacaftor/lumacaftor. 
     
     
         39 . The method of  claim 1 , wherein the human subject has an F508del mutation. 
     
     
         40 - 43 . (canceled) 
     
     
         44 . The method of  claim 1 , wherein the human subject has a forced expiratory volume in one second (FEV1) of between about 50% and 90% of predicted normal. 
     
     
         45 . (canceled)