Pharmacodynamics of recombinant human diamine oxidase

Anaphylaxis is a reaction of the body to drugs, insect bites, food or other unknown environmental agents. These triggers cause an explosive release of histamine from cellular storage sites, which can have life-threatening consequences. Blood vessels dilate and the heart struggles with maintaining blood circulation. In the worst case, there is a collapse of blood circulation and/or severe respiratory distress. Unfortunately, until now, only combating symptoms is possible, for example by means of artificial adrenalin, which causes the blood vessels to contract again, or antihistamines, which block the docking sites of histamine after ingestion. While adrenaline can cause severe life-threatening side effects and antihistamines can only help with relatively little histamine, our focus is on quickly and completely removing the released histamine. This removes the cause and not just treats the symptoms. One would also need much less or no more epinephrine. The body already has a method of converting histamine to an inactive form: the enzyme diamine oxidase (DAO). This is also released in response to a histamine release, but it is sometimes inactive, or the amount of histamine is simply too large to be broken down in time. Our approach is therefore to support the body in the degradation of histamine by means of artificially generated DAO. Our research group has already succeeded in producing a highly active and very pure diamine oxidase, which, due to a mutation, remains in the blood even longer than the natural one, which is no longer detectable after only a few minutes. Our hypothesis is that we can treat the elevated histamine levels and the resulting problems better with the artificial diamine oxidase than with adrenaline and antihistamines because we are combating the cause. We will test in an animal model with guinea pigs how histamine-induced symptoms can be improved by DAO application. Furthermore, we will calculate how long DAO circulates in the animal body, which will help us to make predictions for an application in humans. Finally, we compare the application of DAO with that of epinephrine and antihistamines, where we expect DAO to degrade histamine and alleviate symptoms both acutely and over time. Targeting histamine as a cause of anaphylaxis in humans may initially seem like the first logical step, but the ability to study this has been limited until now. The diamine oxidase we have developed, with its increased purity and prolonged duration of action, paves the way to a drug for both acute and chronic histamine release.

This project investigated a new approach to treating dangerous histamine reactions using a modified recombinant human diamine oxidase, an enzyme that breaks down histamine and was patented by the Medical University of Vienna. The findings suggest that this enzyme could one day become a more effective treatment for severe allergy-like reactions than current standard options. What was studied The first study (doi: 10.1007/s00011-023-01783-3) tested whether a modified form of the enzyme could block the effects of continuous histamine infusion in guinea pigs. This model was chosen because guinea pigs react to histamine more like humans do than mice or rats. The second study (doi: 10.1007/s00011-026-02297-4) used a more severe model: the guinea pigs received a histamine dose that caused shock, lung failure, and often death. This made it possible to compare the enzyme with adrenaline, a currently recommended but still insufficiently proven therapy for anaphylaxis. Main findings In both studies, the enzyme reduced the amount of histamine in the blood and lessened the harmful effects it caused in the body. In the first paper, it reduced rapid heart rate and softened the drop in body temperature. In the second paper, it not only improved heart rate and oxygen levels, but also prevented shock and significantly reduced deaths. These benefits were seen even when the enzyme was given after symptoms had already started. By contrast, intramuscular adrenaline was not effective. Why it matters Histamine is the main trigger of acute, severe allergic reactions such as anaphylaxis. Current emergency treatments like adrenaline, antihistamines, and steroids do not remove histamine itself, which limits their effectiveness in severe cases such as anaphylaxis or severe asthma attacks. These studies point to a different strategy: directly break down the harmful messenger before it can cause further damage. What the results suggest Together, the two papers show that the modified enzyme remained effective even at high histamine concentrations, which can easily overwhelm the effects of antihistamines (doi: 10.1016/j.drudis.2025.104383), helped to define a dose range for human testing, and suggest that the enzyme may outperform adrenaline in severe histamine-induced shock. This is especially important because a recent human trial showed that intramuscular adrenaline failed to reverse histamine-mediated shock in most participants, at histamine levels similar to those seen in grade 4 anaphylaxis after insect stings (doi: 10.1111/all.70277). These findings make the approach promising for future treatment of patients, especially for life-threatening allergic reactions. In plain language You can think of histamine as the "spark" that ignites a severe allergic reaction. These studies tested a biological "fire extinguisher" that removes the spark itself, and in animals it worked better than adrenaline, the recommended emergency medicine for anaphylaxis.