Team:Heidelberg/Integrated
Integrated Human Practices
Interview with Prof. Dr. med Stefan Kölker from the “Dietmar Hopp Stoffwechselzentrum”
New ideas in medical research are essential for developing alternative therapies and thus advancing the medical treatment of diseases. Fundamental laboratory research is necessary for laying a foundation however, it is not everything. One should consider as early as possible to what extent methods, developed in the laboratory, can be implemented in clinical treatment. In order to get feedback for our project from a medical point of view, we met with the pediatrician Prof. Dr. med Kölker from the "Dietmar Hopp Metabolic Center".
We aimed to get an expert's assessment on how far the therapeutic approach we have developed, could be implemented clinically. Furthermore we evaluated where difficulties may appear and whether there are already other approaches. The main purpose of the meeting was to find out which other metabolic diseases our therapy approach could be used for. In metabolic diseases, such as phenylketonuria, which are a particular focus in our project, therapy is started immediately after birth, therefore we talked in particular about the special features of therapy for newborn and children.
The following sections summarize the key insights from the interview with Dr. Kölker
The treatment of phenylketonuria - previous methods, PAL as a new drug and further approaches.
Phenylketonuria (PKU) is an inherited disease where the patient can not degrade phenylalanine. The classic and most efficient therapy for people with PKU is still a diet low in phenylalanine and an additional supply of the essential amino acids.
For patients, this means a strong renunciation in everyday activities such as a visit to a restaurant.
The use of PAL directly has not yet been established as a therapeutic drug in Germany due to dangerous, partly life-threatening, immunological reactions that occur in many patients. This example shows that even if successful results in researching this topic have already been achieved, for physicians it is most decisive how safe a therapy method is.
This medical point of view, that has clearly been emphasized by Dr. Kölker, is: "Safety first!" If physicians have the choice between a therapy that may achieve slightly better results but carries a higher risk for the patient, they will opt for the already established therapy with lower risk.
The researchers goal must be not only to achieve better efficiency with a new therapeutic approach, but also to make new treatment methods as safe and comfortable as the established ones.
Dr. Kölker told us about another drug called Sapropterin, which is already being used in clinical treatment of PKU. It is a cofactor of PAH and can thereby enhance the efficiency of PAH in patients, where the enzyme is present, but only partially functional. Since a decreased functionality of PAH is the exception rather than the rule in PKU, it only leads to therapeutic success for a small group of patients.
With Dr. Kölker we also discussed other research approaches for the treatment of PKU. These include, for example, the modification of erythrocytes in the liver via non-inserting AAV8 vectors. The problem here is, that this treatment needs to be repeated, because non-inserting AAV8 are not suitable for long term treatment. Theoretically inserting AAV8 could be used, but here we have the risk of liver carcinomas. In the future more treatments will probably be possible with the help of mRNA, liposomes and gene therapy.
The use of PAL directly has not yet been established as a therapeutic drug in Germany due to dangerous, partly life-threatening, immunological reactions that occur in many patients. This example shows that even if successful results in researching this topic have already been achieved, for physicians it is most decisive how safe a therapy method is.
This medical point of view, that has clearly been emphasized by Dr. Kölker, is: "Safety first!" If physicians have the choice between a therapy that may achieve slightly better results but carries a higher risk for the patient, they will opt for the already established therapy with lower risk.
The researchers goal must be not only to achieve better efficiency with a new therapeutic approach, but also to make new treatment methods as safe and comfortable as the established ones.
Dr. Kölker told us about another drug called Sapropterin, which is already being used in clinical treatment of PKU. It is a cofactor of PAH and can thereby enhance the efficiency of PAH in patients, where the enzyme is present, but only partially functional. Since a decreased functionality of PAH is the exception rather than the rule in PKU, it only leads to therapeutic success for a small group of patients.
With Dr. Kölker we also discussed other research approaches for the treatment of PKU. These include, for example, the modification of erythrocytes in the liver via non-inserting AAV8 vectors. The problem here is, that this treatment needs to be repeated, because non-inserting AAV8 are not suitable for long term treatment. Theoretically inserting AAV8 could be used, but here we have the risk of liver carcinomas. In the future more treatments will probably be possible with the help of mRNA, liposomes and gene therapy.
Additional diseases and microbiome-based therapeutic approaches
So far, we have mainly focused on PKU as a metabolic disease. Dr. Kölker had drawn our attention to other amino acid metabolism related diseases that could possibly be reached with our approach. These include maple syrup urine disease and Glutaric aciduria. Further considered could be urea cycle disorders, for which liver-based therapies are already in development.
According to Dr. Kölker, it is currently more challenging to develop therapies for fatty acid oxidation disorders because the malfunctions occur in the mitochondria and are thus difficult to reach. Even with our approach of therapy through transformation of the gut microbiome, it will be difficult to reach this area. However, another application we had considered was the lung, since there is also a microbiome and diseases such as cystic fibrosis could possibly be treated there. For questions in this topic area Dr. Kölker referred us to the DLZ ("German Center for Lung Research").
According to Dr. Kölker, it is currently more challenging to develop therapies for fatty acid oxidation disorders because the malfunctions occur in the mitochondria and are thus difficult to reach. Even with our approach of therapy through transformation of the gut microbiome, it will be difficult to reach this area. However, another application we had considered was the lung, since there is also a microbiome and diseases such as cystic fibrosis could possibly be treated there. For questions in this topic area Dr. Kölker referred us to the DLZ ("German Center for Lung Research").
Microbiome-based therapeutic approaches
However, Dr. Kölker also reported on some medically promising microbiome-based therapeutic approaches. One example given is the attempt to inhibit the growth of ammonia-producing bacteria in the intestine as a new approach for treatment of urea cycle disorders. The aim hereby is to prevent the production of additional ammonia, since ammonia levels are strongly elevated in this clinical picture anyway.
Child-orientated forms of application
Dr. Kölker was very pleased with our question about what particularities are required when developing a treatment of children. He and many physicians wish from the pharmaceutical industry to take these questions under consideration. According to him, it has always been criticized by paediatricians that often no child-orientated forms for new medications are provided.
Many drugs are administered in tablet form, which causes major problems in pediatrics, especially in the treatment of newborns. On the one hand, children can only swallow a tablet from a certain age - before that, one has to work with juices or suppository drugs - on the other hand, the dosage has to be much more specifically adapted to the child's developmental state, weight and body size. To address this issue divisible tablets, or even better juices are used. The importance of consistency and taste in the administration of medicines to children should also not be underestimated. A current approach as an alternative to tablets that is being tested in Heidelberg is so-called 2d or 3d printed postage stamps. These are absorbed via the buccal mucosa and thus bypass the first pass of the liver.
Many drugs are administered in tablet form, which causes major problems in pediatrics, especially in the treatment of newborns. On the one hand, children can only swallow a tablet from a certain age - before that, one has to work with juices or suppository drugs - on the other hand, the dosage has to be much more specifically adapted to the child's developmental state, weight and body size. To address this issue divisible tablets, or even better juices are used. The importance of consistency and taste in the administration of medicines to children should also not be underestimated. A current approach as an alternative to tablets that is being tested in Heidelberg is so-called 2d or 3d printed postage stamps. These are absorbed via the buccal mucosa and thus bypass the first pass of the liver.
Our take home message
During the joint considerations on the application in the lung microbiome for the treatment of cystic fibrosis, Dr. Kölker mentioned the drug Pulmozyme®. Pulmozyme® is used to hydrolyze DNA present in mucus in order to make it more fluid. It contains the enzyme DNaseI. We therefore researched to what extent we could have this enzyme expressed by the lung microbiome. We found out that bacteria are not able to express a functional DNaseI. During our search for alternatives, we came across micrococcal nucleases.
In addition, we realized that since our therapy tends to be used in children, we would also have to think about child-friendly forms of application when transporting our DNA via a capsule into the intestine. The first resolution was that a capsule should be used as a one-time treatment. We further talked about the design of capsules which are suitable for children. In the case of supplementaries such as agarose or β-galactose for the selection advantage, one could work for example with gummy bears or sugar containing juices. We brought these new considerations to the MicrobioCOSMOS meetup while discussing ethics in child-treatment and drug design.
In addition, we realized that since our therapy tends to be used in children, we would also have to think about child-friendly forms of application when transporting our DNA via a capsule into the intestine. The first resolution was that a capsule should be used as a one-time treatment. We further talked about the design of capsules which are suitable for children. In the case of supplementaries such as agarose or β-galactose for the selection advantage, one could work for example with gummy bears or sugar containing juices. We brought these new considerations to the MicrobioCOSMOS meetup while discussing ethics in child-treatment and drug design.
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