US2019218556A1PendingUtilityA1

Compositions and methods of inhibiting gene expression in a lung

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Assignee: BHANDARI VINEETPriority: Jun 20, 2014Filed: Dec 27, 2018Published: Jul 18, 2019
Est. expiryJun 20, 2034(~7.9 yrs left)· nominal 20-yr term from priority
Inventors:Vineet Bhandari
A61K 9/0043C12N 15/113A61K 47/24A61K 45/06C12N 15/111A61K 31/713A61K 9/0073C12N 15/1136C12N 2320/32C12N 2310/113C12N 2310/14C12N 2320/30
45
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Claims

Abstract

The present invention provides compositions and methods for delivery to a lung tissue comprising a small interfering RNA (siRNA) capable of inhibiting expression of a gene, and a surfactant. In one aspect, a non-polymeric methods composition comprising a small interfering RNA (siRNA) capable of inhibiting expression of a gene, and a surfactant is disclosed. In other aspects, a method of inhibiting gene expression in a lung of a subject in need thereof and treating bronchopulmonary dysplasia in a lung of a subject also disclosed. The methods comprise administering a therapeutically effective amount of a non-polymeric composition to the lung of the subject, wherein the non-polymeric composition comprises a small interfering RNA (siRNA) capable of inhibiting expression of a gene, and a surfactant.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A non-polymeric composition comprising a small interfering RNA (siRNA) capable of inhibiting expression of a gene, and a surfactant, wherein the composition is formulated for delivery to a lung tissue. 
     
     
         2 . The composition of  claim 1 , wherein the siRNA comprises an RNA that inhibits expression of at least one gene encoding a protein selected from the group consisting of C/EBP homologous protein (CHOP), interferon-gamma (IFN-γ), transforming growth factor-beta 1 (TGF-β1), and angiopoietin 2 (Ang2). 
     
     
         3 . The composition of  claim 2 , wherein the siRNA is selected from the group consisting of a CHOP siRNA, an Ang2 siRNA, and an anti-sense made against the mature miRNA34a sequence. 
     
     
         4 . The composition of  claim 2 , wherein the siRNA is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3. 
     
     
         5 . The composition of  claim 1 , wherein the siRNA is an antagomir. 
     
     
         6 . The composition of  claim 5 , wherein the siRNA is a miR34a antagomir. 
     
     
         7 . The composition of  claim 1 , wherein the siRNA comprises an RNA that inhibits expression of at least one gene encoding an anti-inflammatory protein selected from the group consisting of Sirt1, Bcl2, Ang1, Tie2, Akt, DLL1, Notch 1, Notch 2, CDK4, Cyclin D1, caspase 3, caspase 8, caspase 9, Fas, and Fas-L. 
     
     
         8 . The composition of  claim 1 , wherein the surfactant comprises a phospholipid. 
     
     
         9 . The composition of  claim 8 , wherein the phospholipid comprises phosphotidylcholine or derivatives thereof. 
     
     
         10 . The composition of  claim 1 , wherein the composition is formulated for intranasal administration. 
     
     
         11 . The composition of  claim 1 , wherein the composition is formulated for administration by inhalation. 
     
     
         12 . The composition of  claim 1  further comprising an inhibitor of cox-2. 
     
     
         13 . A method of inhibiting gene expression in a lung of a subject in need thereof comprising:
 administering a therapeutically effective amount of a non-polymeric composition to the lung of the subject, wherein the non-polymeric composition comprises a small interfering RNA (siRNA) capable of inhibiting expression of a gene, and a surfactant.   
     
     
         14 . The method of  claim 13 , wherein the siRNA inhibits gene expression of at least one anti-inflammatory molecule selected from the group consisting of Sirt1, Bcl2, Ang1, Tie2, Akt, DLL1, Notch 1, Notch 2, CDK4, Cyclin D1, caspase 3, caspase 8, caspase 9, Fas, and Fas-L. 
     
     
         15 . The method of  claim 13 , wherein the siRNA inhibits gene expression of at least one molecule selected from the group consisting of C/EBP homologous protein (CHOP), interferon-gamma (IFN-γ), transforming growth factor-beta 1 (TGF-β1), and angiopoietin 2 (Ang2). 
     
     
         16 . The method of  claim 13 , wherein the siRNA is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3. 
     
     
         17 . The method of  claim 13 , wherein the administration delivers the composition to alveoli in the lung. 
     
     
         18 . The method of  claim 13 , wherein the composition is formulated for inhalation administration or intranasal administration. 
     
     
         19 . The method of  claim 13  further comprising administering an inhibitor of cox-2. 
     
     
         20 . The method of  claim 13  further comprising assessing dysregulated vascularization in the lung. 
     
     
         21 . The method of  claim 13 , wherein the lung is hyperoxic. 
     
     
         22 . The method of  claim 13 , wherein the subject has bronchopulmonary dysplasia. 
     
     
         23 . The method of  claim 13 , wherein the subject has hyperoxia-induced cell death in the lung. 
     
     
         24 . A method of treating bronchopulmonary dysplasia in a lung of a subject comprising:
 administering a therapeutically effective amount of a non-polymeric composition to the lung of the subject, wherein the non-polymeric composition comprises a small interfering RNA (siRNA) capable of inhibiting expression of a hyperoxia-induced gene, and a surfactant.

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