Silencing IBD: when a tiny molecule can make a great difference.

New DealConsortium, Inflammatory bowel diseases, New DealLeave a Comment

Take a quick look on your body. We are a combination of one hundred thousand billion cells. Inside each one of them, we can find all our DNA that holds more than twenty thousand genes. DNA remains in the cell nucleus and, when its information is needed, it doesn’t leave it. Instead, it is transcribed in a different kind of molecules known as messenger RNA or mRNA. These molecules are released out of the cell nucleus to be translated into proteins: the basic molecular bricks involved in most of cell vital functions. The process by which the genetic information, coded as DNA, is converted into these functional proteins is called gene expression.

But not all our cells are identical. Brain cells don’t have the same function than skin cells, so they don’t need to express skin cell-related genes. There are some ways to switch off the expression of these genes, and one of them is RNA interference (RNAi). “RNAi is a natural event that happens in the cells, driven by molecules called microRNAs (miRNAs). They bind to mRNAs and trigger their degradation”, explains Dr Xavier Gidrol, partner of New Deal project and manager of the Biomics Laboratory and the Large-Scale Biology Unit at CEA Grenoble (France). If mRNAs are destroyed, they cannot be translated, and the protein they code for will not be produced. Thus, RNAi acts without altering the information that the genes hold, but merely impeding its conversion into proteins.

“This natural process has been mimicked by using artificial small interference RNAs (siRNAs) that do the same effect as the natural miRNAs.”, says Dr Gidrol. Nature is one of the most important inspiration sources for scientists. New Deal’s goal is to use the therapeutic effects of siRNAs to treat inflammatory bowel diseases (IBD), a term that englobes ulcerative colitis and Crohn’s syndrome. Only in Europe, over 2 million people are affected by one of these diseases. In them, the expression of genes JAK1 and JAK3 triggers an undesired inflammation. “Putting siRNAs in cells significantly decreases the number of mRNAs they target so that the protein is no longer there, or it is so dispelled it doesn’t work properly. JAK1 and JAK3 proteins will not be efficient anymore and eventually we will get less inflammation”,  explains Dr Gidrol.

siRNAs therapies share the same goal than the therapeutics used previously to fight IBD, which is to reduce the activity of these proteins, but they do it differently. Traditional chemical inhibitors bind to a target protein and block its activity, while siRNAs straightaway avoid proteins to be synthesized by binding to mRNAs and triggering their degradation. Moreover, siRNAs have the advantage of being more specific as they are designed to target only the sequence of the messenger from the gene that we are interested in switching off. Gidrol’s group role in New Deal project is the computational design of siRNAs: “We have been using our own algorithm, called DESIR, to design siRNAs to specifically target JAK1 and JAK3. It was conceived in order to reduce the off-target effect”, explains Dr Gidrol. This effect happens when a siRNA binds to a different messenger than the one it was designed for, so it would switch off other genes and thus generate secondary effects.

Specificity makes siRNA a robust therapy, but there is an inconvenience. “The difficulty so far to get siRNAs into the clinic is delivery”, clarifies Dr Gidrol. In the early 2000s, researchers were using naked siRNAs and putting them into the cells, but they didn’t last for a long time as these molecules are sensitive to enzymes that degrade nucleic acids. In order to avoid this situation, it is important to protect the siRNAs. In the New Deal project, the therapeutic agent is delivered using lipid nanoparticles that shield the siRNA molecules they carry inside.

Nowadays, the most popular treatment for IBD, as it is for other diseases, is still protein therapies based on antibodies. This kind of treatments meant a revolution when they were implemented in the clinic. But there is already a siRNA therapeutic available in the market for transthyretin-mediated amyloidosis disease. “My feeling is that there will be more siRNA in the market in the future. If one looks at the protein therapeutics, first people in the pharmaceutical industry thought antibody therapies would never work! But, eventually, it worked”. siRNAs may follow the same path and become the next clinical revolution.

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