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US-12618067-B2 - Targeted delivery of an inhibitor of miR-21 to macrophages for the treatment of pulmonary fibrosis

US12618067B2US 12618067 B2US12618067 B2US 12618067B2US-12618067-B2

Abstract

The present invention relates to a composition for use in the treatment of pulmonary fibrosis of a subject, wherein the composition comprises an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 to a macrophage. Further, the composition may be administered by a pulmonary administration. In particular aspects, said subject to be treated suffers from pulmonary fibrosis and further has a lung disease or disorder, wherein the lung disease or disorder may be a corona virus disease. Furthermore, the invention relates to a composition, wherein the composition comprises an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 to a lung macrophage.

Inventors

  • Stefan Engelhardt
  • Deepak Prabhu RAMANUJAM

Assignees

  • Technische Universität München

Dates

Publication Date
20260505
Application Date
20210409
Priority Date
20200409

Claims (17)

  1. 1 . A method of treating pulmonary fibrosis associated with and/or caused by a viral infection, the method comprising administering to a subject in need thereof a composition comprising an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 selectively to a lung macrophage, wherein said moiety comprises mannose, wherein the inhibitor of miR-21 is conjugated to said moiety via a linker, and wherein: (i) the linker is: wherein * represents a bond to the moiety that delivers said inhibitor of miR-21 selectively to a lung macrophage and ** represents a bond to the inhibitor of miR-21; and/or (ii) the moiety that delivers said inhibitor of miR-21 to a macrophage is: wherein the linker is attached at the anomeric carbon at the lower right hand part of the structure.
  2. 2 . The method of claim 1 , wherein the selectively delivery means a selective and preferential binding to said macrophage over non-target cells.
  3. 3 . The method of claim 1 , wherein the composition is administered by a pulmonary administration.
  4. 4 . The method of claim 3 , wherein the composition is administered by an aerosolized composition to the lung of the subject by inhalation or by other means of local administration to the lung, bronchi and/or airways.
  5. 5 . The method of claim 1 , wherein the viral infection is a corona virus infection.
  6. 6 . The method of claim 1 , wherein the pulmonary fibrosis is associated with and/or caused by pulmonary support or mechanical ventilation, optionally following Adult/Acute Respiratory Distress Syndrome (ARDS).
  7. 7 . The method of claim 1 , wherein the composition is administered to the subject at least about 5 days after Adult/Acute Respiratory Distress Syndrome (ARDS).
  8. 8 . The method of claim 1 , wherein the composition is administered by intraarterial administration.
  9. 9 . The method of claim 1 , wherein the inhibitor of miR-21 comprises or is an antisense miRNA-21.
  10. 10 . The method of claim 9 , wherein the antisense miRNA-21 is an oligonucleotide that comprises a sequence complementary to miR-21.
  11. 11 . The method of claim 9 , wherein the antisense miRNA-21 is a locked nucleic acid (LNA) or a phosphorothioated LNA/DNA mixmer.
  12. 12 . The method of claim 1 , wherein the inhibitor of miR-21 is selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 7, SEQ ID NO:8 and SEQ ID NO: 9.
  13. 13 . The method of claim 1 , wherein the composition contains the following compound, wherein the LNA-antimiR-21 is SEQ ID NO:1:
  14. 14 . The method of claim 7 , wherein the composition is further to be administered to the subject at least about 19 days after Adult/Acute Respiratory Distress Syndrome (ARDS).
  15. 15 . The method of claim 8 , wherein the composition is administered by intracardial administration, intracoronary administration, and/or by administration via inhalation.
  16. 16 . The method of claim 12 , wherein the inhibitor of miR-21 is bound to the linker via the phosphor atom of a terminal phosphorothioate group.
  17. 17 . The method of claim 1 , wherein the linker is: wherein * represents a bond to the moiety that delivers said inhibitor of miR-21 selectively to a lung macrophage and ** represents a bond to the inhibitor of miR-21; and the moiety that delivers said inhibitor of miR-21 to a macrophage is: wherein the linker is attached at the anomeric carbon at the lower right hand part of the structure.

Description

This application is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/EP2021/059360, filed Apr. 9, 2021, the entire contents of which are hereby incorporated by reference. International Application No. PCT/EP2021/059360 claims benefit of European Application No. 20169160.7, filed Apr. 9, 2020. The present invention relates to a composition for use in the treatment of pulmonary fibrosis of a subject, wherein the composition comprises an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 to a macrophage. Further, the composition may be administered by a pulmonary administration. In particular aspects, said subject to be treated suffers from pulmonary fibrosis and further has a lung disease or disorder, wherein the lung disease or disorder may be a corona virus disease. Furthermore, the invention relates to a composition, wherein the composition comprises an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 to a lung macrophage. There is a high need of the treatment of organ fibrosis, for example pulmonary fibrosis. With regard to pulmonary fibrosis, viral infections, such as the corona virus infections, like COVID-19, are often followed by consolidation of the lung and fibrosis (Xu et al., 2020). Pulmonary fibrosis severely compromises pulmonary function and is largely untreatable with the current treatment and treatment regimens (Sgalla et al., 2018). Therefore, there is also an urgent need for new therapeutic strategies targeting alternative mechanisms and molecules involved in pulmonary fibrosis. Furthermore, fibrosis plays further key roles in the pathologies of further diseases, such as cardiac diseases or disorders. Although acute survival after myocardial infarction has considerably improved within the last decades (Bahit et al., 2018), post-ischemic heart failure (HF) remains a very frequent (approx. 50%) consequence and constitutes one of the most common causes for hospitalization and death (Bahit et al., 2018). While current medical management of HF largely relies on vasodilating agents and inhibitors of neurohumoral activation, the clinical efficacy of these therapeutic principles has been suggested of having reached a level, where further increases in clinical benefit are increasingly difficult to achieve (Pellicori et al., 2019). Still, there is an urgent need for new therapeutic strategies targeting alternative mechanisms and molecules involved in HF pathology. Microribonucleic acids (MiRNAs or miRs) are approximately 20-22 nucleotides long RNA molecules that bind to antisense complementary regions in the 3′-untranslated regions of the majority of protein-encoding mRNAs (Bartel, 2018). Next to their pivotal role in almost any cellular process investigated to date, they are important regulators in a large and growing list of disease entities, including cancer, immunological and cardiovascular disease (Mendell & Olson, 2012). A major obstacle, which till date prevented the clinical development of inhibitors of miR-21, in particular oligonucleotide-based therapies, is the relatively low extent to which these molecules enter cells upon systemic delivery. Consistently, the prior art suggests to use comparably high doses of oligonucleotides, ranging from 2-80 mg/kg body weight. Such doses cannot be scaled to humans, both for economic reasons and for side effects that can be expected with such high substance loads (Li & Rana, 2014; Lu & Thum, 2019). Accordingly, the underlying technical problem is the provision of an improved therapy of pulmonary fibrosis. The technical problem is solved by provision of the embodiments provided herein below and as characterized in the appended claims. In particular, and as documented in the appended examples, it was surprisingly found that inhibition of miR-21 reduces pulmonary remodeling and/or dysfunction in diseased and/or damaged lungs. Accordingly, the present invention relates to the medical and/or pharmaceutical use of an inhibitor of miR-21 in the treatment and/or amelioration of a lung disease, a lung damage and/or of a lung disorder. Said lung disease, said lung damage and/or said lung disorder may be, may be the cause of and/or may be accompanied by pulmonary fibrosis. In a particular embodiment, the present invention relates to a composition for use in the treatment of pulmonary fibrosis, wherein said composition comprises an inhibitor of miR-21 and a moiety that delivers said inhibitor of miR-21 to a macrophage. In context of this invention the term “composition” also comprises compounds, wherein said “compound” may be a single molecule that has at least two functional moieties/parts, i.e., (a) a functional moiety/part that is an inhibitor of miR-21 and (b) a functional moiety/part that delivers said inhibitor of miR-21 to said macrophage. In context of this invention, the term composition and compound may be used interchangeably. Accordingly, and in one embodiment, said compo