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.