Hereditary angioedema is a chronic disorder that can sometimes be life-threatening. Now, a new drug therapy has been successfully tested in an international study headed by the University Hospital Frankfurt.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent painful swellings of the skin and mucous membranes. Without treatment, patients’ quality of life is noticeably compromised: Angioedema may not only be disfiguring; in the gastrointestinal tract it may lead to severe abdominal colic ad in the upper airways it can even be fatal if left untreated. The frequency of angioedema attacks is unpredictable and varies from patient to patient; swellings may occur up to several times a week. The disorder affects about one to two in a hundred thousand people.
A new drug has been developed to help prevent attacks of hereditary angioedema and at the same offer the patients a convenient administration. It has now been investigated in an international study performed at over 26 university facilities in Europe, Canada and Australia. The results were clear: the drug is highly effective with regard to attack prevention and improvement in quality of life while offering a convenient oral administration. Dr. Emel Aygören-Pürsün, specialist in internal medicine at the Division of Oncology, Hematology and Hemostaseology at the Department for Children and Adolescents of the University Hospital Frankfurt, served as the principle investigator of the study. “Hereditary angioedema is a condition that may be associated with lifelong impairment. With this fundamentally new development, we may reduce HAE- attacks and consistently improve our patients’ quality of life,” explains Dr. Emel Aygören-Pürsün. The HAE competence centre at University Hospital Frankfurt is one of the leading institutions nationwide for patient care and the clinical development of therapies for hereditary angioedema. Professor Thomas Klingebiel, Director of the Department for Children and Adolescents, underlines the significance of the results: “Pioneering patient care and cutting-edge clinical research – these are what University Hospital Frankfurt stand for.” The results of the study have now been published in the renowned New England Journal of Medicine.
Genetic disorder leads to uncontrolled swellings
For most cases of hereditary angioedema, the underlying cause is a congenital deficiency or dysfunction of what is known as C1-inhibitor. As a result of C1-inhibitor deficiency, plasma levels of bradykinin increase, a peptide which locally increases the permeability of the smallest blood vessels.
The central role of bradykinin in the development of angioedema attacks is well established for hereditary angioedema. Attacks of angioedema in patients with hereditary angioedema are related to the action of bradykinin, whose generation is closely linked to another plasma protein, called kallikrein. If kallikrein is active, then bradyinin generation is the result. The inhibition of kallikrein should therefore be a suitable measure for prophylaxis of angioedema attacks.
Therapeutic breakthrough in the form of capsules
So far, the prevention of angioedema attacks in hereditary angioedema was bound to medication that required injections. Although drugs were also available as tablets, these proved either ineffective or were not licensed in many countries. In addition, some of them led to severe side effects and could not be administered to children or during pregnancy.
The new drug BCX7353 tested in the study is a synthetic small molecule that acts as a specific kallikrein inhibitor and is administered as capsules. The aim of the development was to achieve an effective prophylaxis with the distinct advantages of an oral administration yet without the side effects of the oral preparations used previously.
During the study, 77 patients were randomized to groups of four different dose levels or placebo. They took the respective dose once daily for 28 days. The patients noted in their diaries the frequency, localization and severity of the attacks; quality of life was recorded at the beginning and the end of the study using a validated questionnaire. Changes in the frequency of the attacks were investigated, as were the side effects from the treatment and the impact on patients’ quality of life.
The results were positive: With a daily dose of 125 mg and higher, a significant reduction of angioedema attacks was demonstrated. Patients who took 125 mg of BCX7353 per day even experienced a reduction in the frequency of their attacks of almost 75 percent compared to placebo; over 40 percent of patients in that dose group remained completely free of attacks during the study. Also the increase in quality of life was most evident for the 125 mg dose; in addition, not only the number of peripheral attacks was reduced in this group but also those in the gastrointestinal tract. Moreover, the side effects of this dose ranged mild.
Overall, the study was able to clearly corroborate the efficacy of BCX7353 and at the same time provide information about the ideal dosage and tolerability of the new drug. Further studies will now be necessary to verify the efficacy and safety with its long-term administration.
Publication: Aygören-Pürsün, E., et al, Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema, New England Journal of Medicine 2018;379:352-62. DOI: 10.1056/NEJMoa1716995.
Further information: Dr. Emel Aygören-Pürsün MD, Internal Medicine and Hemostaseology, Division of Oncology, Hematology and Hemostaseology, Department for Children and Adolescents, University Hospital Frankfurt, Tel. +49 (0)69- 63 01 63 12 / 63 01 63 44, firstname.lastname@example.org
Range of applications for silicones on the increase thanks to modular, combinable building blocks
FRANKFURT. Silicones are synthetic materials used in a broad range of applications. Thanks to the stability of the silicon-oxygen bond, they are resistant to chemicals and environmental influences and also harmless from a physiological point of view. As a result, silicones contribute to making everyday life easier in almost all areas. In the Journal of the American Chemical Society, chemists at Goethe University Frankfurt have now described a new way to produce long-awaited silicon building blocks in a simple and efficient way.
The broad spectrum of applications for silicones ranges from medical implants and cosmetics to hydraulic oils and sealants to corrosion protection – an important topic in view of global corrosion damage to the tune of about US$ 3.3 trillion per year. To optimize silicon-based synthetic materials for specific applications, made-to-measure chlorosilane building blocks are required in order to produce and crosslink the long-chain polymers. This influences, for example, the material’s viscosity and flow properties. Completely new challenges are emerging in the area of 3D printing, with the aid of which products such as individualized running shoes can be manufactured.
Since 1940, the Müller-Rochow Direct Process has formed the backbone of the silicone industry. In this process, elementary silicon is converted with methyl chloride into methylchlorosilanes at high temperatures and pressures in the presence of a copper catalyst. The working group led by Professor Matthias Wagner at the Institute of Inorganic and Analytical Chemistry of Goethe University Frankfurt has now developed a complementary process that has several advantages over the Direct Process: It uses hexachlorodisilane and chlorinated hydrocarbons as starting materials. “Hexachlorodisilane is already mass-produced for the semiconductor industry and the perchlorethylene (PER) we use particularly frequently is a non-flammable liquid which is so inexpensive that it’s used worldwide as a solvent for dry cleaning,” says Matthias Wagner. In addition, the process runs at room temperature and under normal pressure. To activate it, just a small concentration of chloride ions is needed in place of a catalyst.
“Our process produces highly functionalized organochlorosilanes that are ideal crosslinkers. In addition, their special structure offers excellent possibilities to adjust the mechanical flexibility of the silicon chains as desired,” explains co-inventor Isabelle Georg, whose doctoral dissertation is being sponsored by the Evonik Foundation. Julian Teichmann was also involved in the project. He confirms that above all the close collaboration between Goethe University and Evonik had a tremendous influence on his training: “Regular discussion of our results with Evonik’s industrial chemists opened my eyes from the beginning to economic constraints and ecological requirements. It was fascinating to follow the path from our discoveries in the lab via the patenting procedures to realization on a technical scale in practice.”
The chemists in Frankfurt believe that their monomers’ special potential lies in the fact that they contain not only silicon-chlorine bonds but also carbon-carbon multiple bonds. The purpose of the former is to construct the inorganic silicon-oxygen chains; the latter can be linked to form organic polymers. This unique combination permits new routes to inorganic-organic hybrid materials.
Publication: I. Georg et al: Exhaustively Trichlorosilylated C1 and C2 Building Blocks: Beyond the Müller-Rochow Direct Process, in: J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.8b05950
Further information: Professor Matthias Wagner, Institute of Inorganic and Analytical Chemistry, Riedberg Campus, Tel.: ++49(0)69-798-29156, Matthias.Wagner@chemie.uni-frankfurt.de
National and regional governments pledge total of around € 97 million for LOEWE Centre “Frankfurt Cancer Institute”
FRANKFURT. Goethe University has a new LOEWE Centre under its belt – together with its own research building that is planned for completion by 2023. As announced on 29 June, a good € 73.4 million are being made available for this purpose; the decision followed a recommendation by the German Council of Science and Humanities in April 2018. Hessen’s State Ministry for Higher Education, Research and the Arts had officially announced just the day before that the Frankfurt Cancer Institute would be integrated as a LOEWE Centre in the state’s scientific support programme. Around € 23.6 million in regional funding are available for operating costs in the first phase from 2019 to 2022.
LOEWE Centre “Frankfurt Cancer Institute”
Nowadays, it is possible to completely decode cancer genes within just a few days. However, to be able to forecast how well a patient will respond to treatment, genetic data are only useful to a limited degree because for this it is necessary to know the effect of mutations within the tumour cell and in turn what impact this will have on the surrounding tissue and the immune system. Exploring this complex process is the task of the LOEWE Centre “Frankfurt Cancer Institute” (LOEWE FCI), where basic researchers and clinicians will work closely together in interdisciplinary teams. Partners from the pharmaceutical industry are also involved. Particularly gratifying is the news that the Frankfurt Cancer Institute will receive a new building on Niederrad Campus paid for by the national government: € 73.4 million have now been approved. According to a press release by Hessen’s State Ministry for Higher Education, Research and the Arts, the national and regional governments are each contributing 50 % towards € 52.1 million of this sum; German Cancer Aid will donate € 20 million towards building costs and additional funds will come from other partners.
“The two grants mean tremendous progress for university medicine in Frankfurt, especially for oncology. Translational cancer research at Goethe University has seen a very positive development in the last ten years. These efforts are now being rewarded by Hessen’s state government and German Cancer Aid in the shape of the new LOEWE Centre and the new research building, for which we’re very grateful. It raises our work to a new level,” says Professor Florian Greten, Director of the Georg Speyer Haus and professor for tumour biology at the Faculty of Medicine of Goethe University.
Apart from Goethe University, also participating in the project are the Georg Speyer Haus (GSH), the German Cancer Consortium (DKTK), the Paul-Ehrlich-Institut (PEI) and the Max Planck Institute for Heart and Lung Research in Bad Nauheim.
“Congratulations to our researchers on Niederrad Campus, who following the approval of the LOEWE jurors have now also been given the green light for their new building by the Joint Science Conference of the state ministry responsible here in Hessen and the federal government in Berlin,” says Professor Birgitta Wolff, President of Goethe University. She is very pleased about the double success. “The Frankfurt Cancer Institute will perform a task that is very important for the future. It will contribute not only to our scientific understanding of cancer but also to its more targeted treatment. This requires staying power and an opportunity to bring together the corresponding disciplines on a long-term basis. We’re very grateful to the national and regional governments for enabling us to establish the necessary framework. The funds for our own new research building are an important milestone that will give cancer research here in Frankfurt a tremendous boost. I’m very happy that Hessen’s state government initiated the LOEWE programme: It’s an indispensable instrument for developing large-scale research programmes at our region’s universities and keeping them running over a long period.”
Funding applications with good prospects
Thanks to the positive evaluation of their preliminary proposals, a further three projects were invited to submit full proposals in the 12th round of funding:
Further information on the LOEWE Centre “Frankfurt Cancer Institute”: Professor Florian Greten, Director of the Georg Speyer Haus, Faculty of Medicine, Goethe University, Tel.: +49(0)69-63395-183, Greten@gsh.uni-frankfurt.de.