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With an European grant of eight million euro an international consortium, coordinated by Radboudumc, will investigate whether congenital hyperinsulinism can be treated with an innovative light therapy.
"It is a frightening disease for babies and children, and it is very stressful as well for parents, family members and close acquaintances," says Martin Gotthardt, professor of Experimental Nuclear Medicine at Radboudumc. He characterizes the rare condition congenital hyperinsulinism (CHI), in which beta cells in the pancreas secrete too much insulin. The result is too little sugar in the blood (a hypoglycemia, or hypo for short), which can cause sweating, shaking, headaches, hunger, dizziness, blurred vision and heart palpitations. If a hypo is not recognized in time - a major risk in babies who cannot tell what they are suffering from - there is even a risk of seizures, unconsciousness, permanent brain damage or death. Thus, 25 to 50 percent of babies with congenital CHI are diagnosed (too) late, leaving them with brain damage such as intellectual disability or cerebral palsy for the rest of their lives.
Eight million euros
Recently Gotthardt, colleague Sanne van Lith and an international consortium received an 8 million euro grant to investigate whether the disease is treatable. Gotthardt: "It’s all about the diffuse form of the disease, not the focal form. In the focal form, all pathogenic beta cells are located together as a clump. In most of the times these can be removed by a complex surgical procedure. In the diffuse form, those pathogenic beta cells are scattered all over the pancreas and surgery is not an option. Sometimes medication can alleviate the problems but most of the time no treatment works. With the LightCure project, sponsored by the European Union, we are trying to develop a complete new therapy for this group of children."
Beta cells in focus
Decades of fundamental research preceded this project. After all, the important question is: how do you get an image of these scattered beta cells in the pancreas. As part of diabetes research - where beta cells actually secrete too little insulin and partially disappear - Gotthardt developed a tracer that visualized beta cells better than ever before. That tracer consists of a small protein, exendin, that binds specifically to a protrusion, a receptor on the beta cell. Gotthardt: "By attaching a radioactive substance to exendin, we got a very good image of the distribution of beta cells in the pancreas. This accurate imaging was necessary for the next step."
Double protection
If exendin binds specifically to beta cells, you might use it to deliver drugs there as well. Van Lith: "We are not using a drug, but a light-sensitive substance that has no biological effect in itself. That changes immediately when you irradiate this substance with laser light of a certain wavelength. Oxygen radicals are then produced that damage or destroy only the cells to which the light-sensitive substance is bound, while the surrounding cells remain intact. We have tested this procedure in mice where it works extremely well. It is actually a double-security therapy, in which exendin first selects the beta cells, and the light-sensitive substance becomes active only after local irradiation with laser light. Together with other hospitals, research institutions, companies and the American-based patient association, we want to take the step toward an effective targeted photodynamic therapy in humans in this LightCure project."
Insulinomas first
In developing this therapy, the consortium will first zoom in on insulinomas in adults. These are neuroendocrine tumors in the pancreas that produce too much insulin, similar to the CHI disease in babies. Van Lith: "Insulinomas are usually benign tumors that can be removed surgically. We first test the approach on excised insulinomas, i.e. outside the body. If this goes well, we then expose the insulinomas inside the body to laser light, to see the results. In parallel, we also investigate what the right dose should be for treatment, because you want an effective treatment without unintended damage. Then determining the optimal dose is very important. Moreover, we constantly monitor whether the treatment is accompanied by any toxic effects to the body."
Inside the body, outside the pancreas
In human tissue, laser light penetrates about 1 centimeter deep. That may also require modifications to endoscopic tools to expose insulinomas and overactive beta cells in the body. Gotthardt: "In adults, it probably means going inside the pancreas with a laser endoscope. In babies, the pancreas is still so incredibly small that we can probably reach any location if we expose just outside the pancreas. But that too is part of this comprehensive project, which all together will take six years."
Innovative approach
Light-sensitive therapy has been used for some time, but mainly for skin conditions. "But that really works very differently from the approach we are taking now," says Gotthardt. "Treatment of skin disorders involve light-sensitive substances that get into the whole body and often have a lot of side effects. We work with a substance that goes exactly to the spot that needs to be treated and then use laser light to determine exactly where and when that substance becomes active. That's really a very different form of light therapy. This form of targeted photodynamic therapy has never been done for CHI."
Platform for many other treatments
With the development of this light therapy for CHI, treatments for other conditions are also coming into view. Van Lith: "It's actually a new platform for many more treatments, because you can vary the substances that selectively bind to cells you want to treat. In addition, you can use different light-sensitive substances for the optimal treatment effect. On the latter point, we are already working closely with Dennis Löwik of Radboud University. We are currently developing similar light therapies for pancreatic cancer and prostate cancer. In the LightCure project, we want to provide proof that this approach really works. It should become a proof of concept that congenital hyperinsulinism can be effectively treated in this way."
Earlier diagnosis and psychosocial consequences
Within the project, we are also working with the patient association CHII to disseminate knowledge and increase alertness to the condition within the healthcare system, so diagnosis can be made earlier. Gotthardt: "In addition, we will conduct scientific research into the psychosocial consequences of the disease and the burden of disease for patients and families, an almost unexplored area. The patient association Congenital Hyperinsulinism International, full partner in the project, has already set up a database for research into the disease in which all affected children are included. From the LightCure project, we support its further development."
The LightCure consortium consists of Radboudumc, Erasmus MC, Charité Universitaetsmedizin Berlin, Hochschule für Angewandte Wissenschaften Hamburg, Medizinische Universitaet Wien, piCHEM Forschungs- und Entwicklungs GmbH Austria, TRACER Europe B.V., Patients Association CHII (Congenital Hyperinsulinism International, VS), Queen Mary University of London, Great Ormond Street Hospital for Children, University College London and Radboud University
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Pieter Lomans
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