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EP-4735594-A1 - USE OF A MIR-27-5P MIMIC FOR TREATING CHRONIC INFLAMMATORY BOWEL DISEASES (IBD)

EP4735594A1EP 4735594 A1EP4735594 A1EP 4735594A1EP-4735594-A1

Abstract

The present inventors have found that a molecule mimicking miR-27a-5p is capable of strongly modulating the inflammatory response in a well-known animal model of inflammatory bowel disease (IBD). Therefore they propose incorporating this mimic into a pharmaceutical composition for treating patients suffering from this disease. Advantageously, this mimic can be linked to a matrix, incorporated into particles, or conveyed by a vector.

Inventors

  • KANSAU, Imad
  • KOBEISSY, Hussein
  • LARRAZET, Cécile
  • MARVAUD, Jean-Christophe

Assignees

  • Université Paris-Saclay
  • Assistance Publique - Hôpitaux de Paris

Dates

Publication Date
20260506
Application Date
20240701

Claims (10)

  1. 1. Pharmaceutical composition containing a double-stranded miR-27a-5p mimic RNA for use in treating a subject suffering from chronic inflammatory bowel disease (CIBD), and wherein said miR-27a-5p mimic RNA contains at least 5, 6, 7 or 8 of the 8 consecutive nucleotides AGGGCUUA.
  2. 2. Pharmaceutical composition for use according to claim 1, wherein said miR-27a-5p mimic RNA contains the sequence AGGGCUUA.
  3. 3. Pharmaceutical composition for use according to claim 1 or 2, wherein said miR-27a-5p mimic RNA contains two RNA strands of respective sequences SEQ ID NO: 2 and SEQ ID NO: 3.
  4. 4. Pharmaceutical composition for its use according to one of claims 1 to 3, further comprising a pharmaceutically acceptable excipient.
  5. 5. Pharmaceutical composition for its use according to one of claims 1 to 4, in which said miR-27a-5p mimic RNA is associated with or included in a vector, a matrix or particles promoting its stability and/or its transfection.
  6. 6. Pharmaceutical composition for use according to claim 5, wherein said vector is chosen from: adenoviruses, retroviruses, lentiviruses, adeno-associated viruses (AAV), herpes viruses, cytomegaloviruses (CMV), and vaccinia viruses.
  7. 7. Pharmaceutical composition for its use according to claim 5, in which said particles are chosen from: liposomes (DOPC), lipid nanoparticles, nanocells, silica nanoparticles, exosomes.
  8. 8. Pharmaceutical composition for its use according to claim 5, in which said matrix is chosen from neutral lipid emulsion (NLE), polyethylenimine (PEI), poly(lactide-co-glycolide) (PLGA).
  9. 9. Pharmaceutical composition for its use according to one of claims 1 to 4, for preventing or treating colon cancer induced by an M ICI.
  10. 10. Pharmaceutical composition for its use according to one of claims 1 to 9, characterized in that the pharmaceutical composition is in a form suitable for intravenous administration.

Description

Use of miR-27-5p mimic to treat chronic inflammatory bowel disease (IBD) Description of the prior art Chronic inflammatory bowel diseases (or IBD) include Crohn's disease (CD) and ulcerative colitis (UC). Both are characterized by inflammation of the wall of a part of the digestive tract. In CD, this inflammation can be located at any level of the digestive system, from the mouth to the anus, although it is most often found in the small intestine. In UC, it is located in the rectum and colon. IBD is most often diagnosed in young people, aged 20 to 30. However, it can occur at any age and 15% of cases concern children. These diseases develop through inflammatory flare-ups of extremely variable duration and frequency depending on the patient. These flare-ups alternate with phases of remission. In approximately 20% of patients, the attacks are severe: their intensity can require hospitalization, stopping of food and treatment by perfusion for a few days. In addition, the progression of the disease can lead to complications requiring surgical intervention. There is no curative treatment for IBD. Currently available anti-inflammatory drugs provide partial control, the aim being to prevent the onset of flare-ups and prolong the remission phases by promoting the healing of lesions in the digestive tract. Biotherapies currently used for the treatment of IBD have improved the quality of life of patients and reduced their hospitalization as well as side effects compared to corticosteroids. However, this use is not without risks. Indeed, many unexpected toxicity problems have occurred and have been recognized as being related to biotherapies, such as with anti-TNFs which cause worsening of heart failure as well as reactivation of mycobacterial infections; or anti-integrin antibodies including natalizumab, with rare cases of lethal viral encephalitis or even excessive cytokine release syndrome, observed in healthy volunteers treated with a monoclonal antibody directed against CD28. In addition, the use of certain biotherapies could also be associated with long-term toxicity, including the development of lymphomas in patients treated with infliximab (anti-TNF). On the other hand, most biologic agents are immunogenic and therefore may lose their effect over time. Furthermore, most patients treated with biologic agents require induction and maintenance therapy and the cost of these agents is likely to remain high. Thus, a balance between efficacy and safety must be carefully considered for each patient [1], Despite the numerous therapeutic approaches developed to date for the management of intestinal inflammation in the context of IBD, medical needs remain unmet: 1) loss of activity of molecules over time, requiring the change of molecule, 2) medium and long-term side effects, including immune disruption, development of cancers, particularly colon cancers, 3) lack of response in refractory forms. There is therefore an urgent need to identify more effective treatments to treat patients with IBD, with the best possible tolerance or with the least possible adverse effects. Several teams have reported the beneficial role that miRNA could have in regulating inflammation associated with IBD [2]. MicroRNAs (miRNAs or miRs) are non-coding RNA sequences of 21 to 24 nucleotides, responsible for the post-transcriptional regulation of genes by their specific action on mRNAs. They can modulate the innate response by regulating different signaling pathways [3]. The fine regulation exerted by miRNAs by their action on several effector and/or regulatory molecules of the same signaling pathway, represents a major advantage of this therapeutic approach since it allows a less drastic decrease in the level of expression of one or more target genes without completely inhibiting them, unlike direct molecular approaches (e.g. small molecules, biotherapies by monoclonal antibodies or others) which act on their direct and universal target by strongly blocking their activity. This aspect is very important in the case of drugs intended for the treatment of inflammation in IBDs, since, in patients suffering from these diseases, the inflammatory response is a universal physiological response whose actors, whether they are effectors of signaling pathways, regulators or end products including cytokines, are ubiquitous and present in different tissues. Thus, a fine and targeted regulation of the expression of these genes by a given miRNA allows a less significant reduction of the corresponding effector proteins without completely destroying them, which consequently limits the significant adverse effects observed during the use of conventional anti-inflammatory treatments. Unfortunately, there are still many gray areas in the understanding of the modulation networks linked to each miRNA. Their non-specificity (each miRNA targeting a multitude of genes) could also induce side effects in the individual to whom it is administered. The identification of a m