Compositions and methods for delivery of RNA
Inventors
Ramunas, John • MARKOV, Glenn Jeremy • OLSEN, William Gillis • BREWER, KYLE DANIEL
Assignees
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Publication Number
US-12721818-B2
Publication Date
2026-09-01
Expiration Date
Abstract
The lipid nanoparticle compositions provided herein preferentially deliver and/or transfect the lung. Also provided herein are therapeutic polynucleotides, e.g. TERT mRNA, which may be delivered with the LNP formulations for the treatment of lung disease and fibrosis.
Core Innovation
The invention relates to delivering polynucleotide RNA to the lung of a subject using a pharmaceutical lipid nanoparticle (LNP) composition. The LNP includes an insulator lipid, cholesterol, an ionizable lipid comprising SS-OP or an SS-OP analog, and a permanently cationic lipid, with a liposomal pKa between about 5.5 and 7.2. In some embodiments, the composition further includes a structural lipid, and the RNA is encapsulated in the LNP.
The RNA encodes telomerase reverse transcriptase (TERT) mRNA having one or more modified nucleotides. The LNP preferentially delivers to the lung compared to liver and/or transfects lung tissue cells compared to liver tissue cells, and telomeres are extended within the lung tissue cells. In related aspects, the composition is substantially free of structural lipids while retaining the defined lipid composition.
The invention further covers a method of treating a lung disease and/or lung fibrosis using an effective amount of the LNP composition. Dependent claims further specify sequence identity to SEQ ID NOS: 38-40, untranslated regions, and alternative RNA forms including self-replicating RNA or circular RNA.
Claims Coverage
Independent claims cover 3 inventive cores: lung delivery using an LNP with defined lipid components and liposomal pKa between about 5.5 and 7.2, treatment of lung disease and/or lung fibrosis using a substantially structural-lipid-free LNP, and a composition comprising encapsulated TERT mRNA. The inventive features center on SS-OP or an SS-OP analog, encapsulated RNA encoding modified-nucleotide TERT mRNA, preferential lung delivery or lung-versus-liver transfection, and telomere extension within lung tissue cells.
Lung-delivery LNP composition with SS-OP ionizable lipid and permanently cationic lipid
A method of delivering a polynucleotide to the lung of a subject using an LNP comprising an insulator lipid, cholesterol, an ionizable lipid comprising SS-OP or an SS-OP analog, and a permanently cationic lipid, with a liposomal pKa between about 5.5 and 7.2.
Encapsulated TERT mRNA with modified nucleotides for telomere extension in lung cells
The LNP encapsulates RNA that encodes telomerase reverse transcriptase (TERT) mRNA having one or more modified nucleotides, wherein the LNP preferentially delivers to the lung compared to liver or transfects lung tissue cells compared to liver tissue cells, and wherein telomeres are extended within the lung tissue cells.
Treatment of lung disease or lung fibrosis using structural-lipid-free SS-OP LNP
A method of treating a lung disease and/or lung fibrosis by administering an effective amount of an LNP composition comprising an insulator lipid, cholesterol, an ionizable lipid comprising SS-OP or an SS-OP analog, and a permanently cationic lipid, where the composition is substantially free of structural lipids, the liposomal pKa is between about 5.5 and 7.2, and the LNP preferentially delivers to lung and extends telomeres in lung tissue cells.
Composition of an SS-OP LNP substantially free of structural lipids encapsulating modified-nucleotide TERT mRNA
A composition comprising an LNP that includes an insulator lipid, cholesterol, an ionizable lipid comprising SS-OP or an SS-OP analog, and a permanently cationic lipid, where the liposomal pKa is between about 5.5 and 7.2, the composition is substantially free of structural lipids, and the RNA is encapsulated and encodes TERT mRNA having one or more modified nucleotides.
Across the independent claims, the core inventive subject matter is lung-focused delivery and treatment using an LNP defined by lipid components and a liposomal pKa of about 5.5 to 7.2, where the encapsulated RNA encodes TERT mRNA with one or more modified nucleotides and results in preferential lung delivery/transfection and telomere extension in lung tissue cells. Additional independent-claim scope includes structural-lipid-free LNP formulations for treating lung disease and/or lung fibrosis, and composition claims that define the LNP formulation and RNA encapsulation.
Stated Advantages
Preferential delivery to the lung compared to liver or transfection of lung tissue cells compared to liver tissue cells.
Telomeres are extended within the lung tissue cells.
Treatment of a lung disease and/or lung fibrosis in a subject in need thereof.
Documented Applications
Delivering polynucleotide RNA to the lung of a subject using an LNP encoding telomerase reverse transcriptase (TERT) mRNA having one or more modified nucleotides.
Treating a lung disease and/or lung fibrosis in a subject by administering an effective amount of the claimed LNP composition.
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