Hitting the bull’s-eye: towards a targeted treatment for IBD

New DealInflammatory bowel diseases, NanotherapyLeave a Comment

When designing a therapy, how the drug will reach the area of the disease is an important matter.  To treat a bruise on our skin we can use a gel to reduce the pain and swelling locally. If we had a headache though, we would need to bring the drug inside the body somehow. For example, an aspirin goes through the gastrointestinal tract and eventually reaches the bloodstream. Using this highway, the analgesic gets distributed throughout the body and can make its effect where it is needed. This strategy is called a systemic administration.

Nevertheless, for some drugs, choosing the delivery strategy is not so simple. For many immune diseases, the most effective therapies are based on drugs that suppress part of the immune response. While this has a therapeutic effect in the affected location, if the drug reaches the bloodstream, it can compromise the immune response in the whole body. This usually leads to side effects like infections that can be even more life-threatening than the disease itself.

This is what happens with intestinal bowel disease (IBD), in which the intestine suffers from chronic inflammation due to some immune cells overreacting. “Small molecule drugs for IBD, like tofacitinib, are absorbed very fast as they can pass through the cellular membrane but administering them systemically produces side effects. That’s why we have chosen a delivery method that allows us to avoid a systemic administration”, affirms Azucena Salas, investigator at the Inflammatory Bowel Disease research group at Institute for Biomedical Research August Pi Sunyer (IDIBAPS). Dr Salas refers to the strategy that the New Deal project proposes: a targeted delivery of the therapeutic molecule. This molecule is called siRNA and it reduces the expression of two proteins closely related to the intestinal inflammation in IBD: the JAK proteins. If you want to know more details about how it works, read our blogpost on the matter.

The question is how to bring the therapeutic molecule to its target without disturbing anything else. The New Deal project to treat IBD locally by combining two elements: a siRNA as a therapeutic molecule and a lipid nanocarrier that delivers it to the intestine without affecting any other body area. “What we seek is a drug that acts in the tissue of interest: the less it affects the rest of the body, the better. This is particularly important with drugs like tofacitinib that target JAK proteins, as they are expressed in cells from different organs and are involved in many processes of the immune system”, explains Dr Salas. The advantage of using nanoparticles as delivery system is that they go inside the intestinal cells very fast, thanks to their chemical properties. Thus, siRNA molecules can make their effect in a controlled way and only in the area of interest.

But finding the right tandem is a hard task: one has to select an effective siRNA and combine it with a nanocarrier that can deliver it successfully into the intestine without leaking into other tissues. The role of IDIBAPS in the New Deal project is to test the candidates, checking that the chosen combinations can fulfil this mission.

They monitor how the combination of siRNA and nanocarrier behaves after it is administered. To do this, they label both elements with fluorescent substances, which make them traceable. They test how the elements act and distribute in mice cells, but also in human adult epithelial stem cells. Moreover, they assess how candidate combinations behave within tissue models. “We use epithelial human tissue organoids based on stem cells from the intestinal crypts. This serves as an approximation to the intestinal cells”, points Dr Salas.

Nevertheless, predicting accurately what will happen when the vehicle enters a living body is impossible. Therefore, the biodistribution and the efficacy of the complex is assessed also by using animal models, in this case, mice. “What we do is to monitor the biodistribution of the complex. This concept alludes to the distribution of a particular drug in a living organism”, states Dr Salas.  However, she adds a clarification: “Animal models do not reflect the complexity of human IBD.” This disease shows diverse and sometimes uneven symptoms and molecular features, so it is difficult to model it in animals. Nevertheless, these models are vital to evaluate the candidate complexes. “They are useful to check the biodistribution and the toxicity of the candidate tandems”, adds Dr Salas. Animal models allow researchers to see if the complex reaches only the intestine after its administration and whether the therapeutic molecule is tackling its molecular target. Thus, they play a key role in the jigsaw puzzle to understand how the complex behaves.

Tuning the complex used in this therapeutic strategy may open the door to exploit other potential targets to better treat IBD. “In an inflamed mucosa there are thousands of disturbed genes, not only JAK. The most interesting part is to get a tool that allows to knock out genes in the mucosa cells.”, explains Dr Salas. The hope is to get a systematic strategy that allows to treat IBD using any molecular target at reach, and beyond, to treat other diseases.


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