Pulmonary delivery of mRNA to non-lung target cells
Inventors
Heartlein, Michael • Guild, Braydon Charles • DeRosa, Frank • Rudolph, Carsten • Plank, Christian
Assignees
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Publication Number
US-11090264-B2
Publication Date
2021-08-17
Expiration Date
Abstract
Compositions comprising mRNA formulated for pulmonary administration and related method for delivery of the mRNA and/or encoded protein to a non-lung cell or tissue. The compositions and methods may be used to prevent or ameliorate the symptoms of diseases associated with the mRNA encoded protein.
Core Innovation
The described invention relates to a method of delivery of messenger RNA (mRNA) to a non-lung cell or tissue by administering to the lung a composition comprising mRNA encoding a protein and a lipid carrier vehicle. The administering to the lung results in delivery of the mRNA to a non-lung cell or tissue. The protein encoded by the mRNA is detectable in the non-lung cell or tissue for at least 6 hours following administration to the lung.
The lipid carrier vehicle comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. The disclosure describes pulmonary administration of lipid-carrier nanoparticle formulations of mRNA and reports delivery and protein expression in non-lung tissues/cells, including liver and hepatocytes, with detectable mRNA/protein in non-lung tissues.
The invention also describes mRNA modification strategies and mRNA features to reduce innate immune recognition and improve stability/translation, including nucleoside modifications and features such as untranslated regions (UTRs), a 5' cap, and a 3' poly(A) tail. The document references in-vivo and bioluminescence imaging (BLI) to support lung-to-systemic protein expression after intratracheal spray or nebulization.
Claims Coverage
The independent claim covers a lung administration method for delivering mRNA to a non-lung cell or tissue, with inventive features centered on the lipid-carrier composition and a measurable detectability duration in the non-lung cell or tissue.
Lung administration of mRNA/lipid-carrier composition to a non-lung cell or tissue with detectability
Administering to the lung a composition comprising mRNA encoding a protein and a lipid carrier vehicle, wherein administering to the lung results in delivery of the mRNA to a non-lung cell or tissue and wherein the protein encoded by the mRNA is detectable in the non-lung cell or tissue for at least 6 hours following the administration to the lung.
Lipid carrier vehicle with cationic, non-cationic, cholesterol-based, and PEG-modified lipids
Using a lipid carrier vehicle comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.
Therapeutic protein encoded by the mRNA
The mRNA encodes a therapeutic protein.
Overall, the claim coverage is directed to delivering mRNA from the lung to non-lung cells or tissues using a defined lipid-carrier vehicle and ensuring that the encoded protein is detectable for at least 6 hours in the non-lung cell or tissue. The dependent refinement specifies that the encoded protein is a therapeutic protein.
Stated Advantages
Enables delivery of mRNA to a non-lung cell or tissue following administering to the lung.
Provides detectable encoded protein in the non-lung cell or tissue for at least 6 hours following lung administration.
Pulmonary administration of encapsulated mRNA using lipid carrier vehicles results in delivery and protein expression in non-lung tissues/cells via translocation across the lung airway-blood barrier.
Documented Applications
Pulmonary delivery of mRNA encoding proteins to non-lung cells or tissues, including liver and hepatocytes.
Delivery supported by intratracheal spray and nebulization with detectable lung-to-systemic protein expression.
Tracking nanoparticle migration/distribution in non-lung organs using fluorescently labeled lipid nanoparticles or radiolabeled mRNA.
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