Related Experiment Video
Updated: May 16, 2026
Therapeutic Evaluation of Fecal Microbiota Transplantation in an Interleukin 10-Deficient Mouse Model
Published on: April 6, 2022
Treatment of experimental murine colitis with CD40 antisense oligonucleotides delivered in amphoteric liposomes
A Arranz1, C Reinsch, K A Papadakis
1Department of Clinical Chemistry, University of Crete Medical School, Crete, Greece.
Background And Aims:
CD40-CD40L interactions appear to play an important role in the pathogenesis of experimental colitis. We tested the effect and investigated the underlying mechanism of action of systemically administered antisense oligonucleotide (ASO) targeting CD40 formulated in amphoteric liposomes (nov038/CD40). The charge characteristics of the amphoteric liposomes (anionic surface charge at physiological pH that becomes cationic at low pH), facilitate efficient sequestration of the ASO inside the liposomes at low pH and the direction of the carriers towards macrophages and dendritic cells under physiological conditions.
Methods:
Colitis was induced in Balb/c mice using 2,4,6-Trinitrobenzene sulphonic acid (TNBS) and treated with nov038/CD40. Disease was monitored by body weight, histology, cytokine profiling and changes in immune cell populations. CD40 expression on different cell subsets was analyzed by flow cytometry. An antigen challenge model was used to determine neoimmunity under CD40 modulation.
Results:
Administration of nov038/CD40 inhibited the development of TNBS colitis as assessed by weight loss, histology and cytokine profiles; unformulated CD40 ASO or nov038 encapsulating an unrelated ASO (nov038/SCR) were ineffective. The novel agent is potent as it completely suppressed even established colitis with a single treatment and significantly reduced T-cell activation as well as levels of pro-inflammatory mediators in serum. The inhibition of CD40 specifically occurred in macrophages, but not in B-cells. In contrast to prednisolone, standard treatment for inflammatory bowel diseases (IBD) that is effective in a single administration and involves extensive immunosuppression, nov038/CD40 did not affect the number of B- or Treg cells. Eventually, we observed a largely intact neoimmunity under conditions of a CD40 inhibition.
Conclusions:
Administration of nov038/CD40, but neither naked CD40 ASO nor nov038/SCR, prevents the development and treats established colitis in mice. Delivery of CD40 ASO in nov038 is highly cell-specific as it selectively suppresses CD40 on macrophages, but not on B-cells; the novel agent has strong anti-inflammatory characteristics without being immunosuppressive.
Insights
A novel liposomal antisense oligonucleotide (ASO) targeting CD40 effectively treats experimental colitis in mice. This targeted therapy suppresses inflammation without causing broad immunosuppression, preserving immune function.
Area of Science:
- Immunology
- Gastroenterology
- Drug Delivery Systems
Background:
- CD40-CD40L interactions are implicated in experimental colitis pathogenesis.
- Antisense oligonucleotide (ASO) targeting CD40 formulated in novel amphoteric liposomes (nov038/CD40) was investigated.
- Amphoteric liposomes facilitate ASO sequestration and target macrophages and dendritic cells.
Purpose of the Study:
- To evaluate the therapeutic effect of systemically administered nov038/CD40 in experimental colitis.
- To elucidate the mechanism of action of nov038/CD40, focusing on CD40 modulation and immune cell populations.
Main Methods:
- Colitis was induced in Balb/c mice using TNBS and treated with nov038/CD40.
- Disease progression was monitored via weight, histology, cytokine profiles, and immune cell analysis.
- CD40 expression, T-cell activation, and neoimmunity were assessed using flow cytometry and an antigen challenge model.
Main Results:
- nov038/CD40 significantly inhibited TNBS colitis development and treated established colitis, unlike unformulated ASO or a scrambled ASO control.
- The treatment potently suppressed T-cell activation and pro-inflammatory mediators, specifically targeting CD40 on macrophages, not B-cells.
- Unlike prednisolone, nov038/CD40 did not deplete B-cells or Treg cells and preserved neoimmunity.
Conclusions:
- nov038/CD40 effectively prevents and treats experimental colitis in mice.
- The liposomal formulation ensures cell-specific delivery, suppressing CD40 on macrophages while sparing B-cells.
- This targeted approach offers potent anti-inflammatory effects without causing generalized immunosuppression.
