About seven boys are born in Germany every year with incompletely formed urethra and bladder sphincter. Despite complicated surgery, the otherwise healthy children often remain incontinent for the rest of their lives. In a clinical trial, researchers from the ECRC, the joint Experimental and Clinical Research Center of the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), now want to test whether the children can be helped by transplanting their own muscle stem cells into the sphincter muscle. The Federal Ministry of Education and Research (BMBF) is funding the study with around 3.3 million euros. The Berlin Institute of Health (BIH) at the Charité has supported the project with its Spark-BIH programme on the way from the laboratory to the clinic with one million euros.
Over 8,000 different rare diseases are known, and over 30 million people are affected in Europe alone. Developing therapies for these diseases, most of which are not yet treatable, is an important task for society and thus a challenge for research. Epispadias is one of them. Here, a prenatal developmental disorder leads to an abnormal position and cleft formation of the urethra and an incompletely formed bladder sphincter. Only about seven boys and even fewer girls are born with this special condition every year in Germany. It is associated with a high degree of suffering: because the externally visible malformation can be corrected with an operation, but unfortunately this is not so easy with the bladder sphincter. „As a result, these children are often incontinent for the rest of their lives, which is associated with a high psychological burden for those affected and their families,“ explains Prof. Dr. Simone Spuler from the ECRC, a specialist in stem cell and muscle research. „We therefore considered how we could help them with our expertise.“
The scientists led by Prof. Spuler had developed a method to isolate regenerative muscle stem cells from muscle tissue. „We take a tissue sample, a biopsy, from the thigh and isolate muscle stem cells from it. We then multiply these many times over and inject them directly into the defect site of the bladder sphincter.“ In rats, this actually led to the formation of a new sphincter muscle that was also functional. Since their altered immune system tolerated human cells, this also succeeded with human muscle stem cells.
„But despite these encouraging results, we could not immediately start a clinical trial with affected people,“ explains the medical doctor. „This is because the regulations are strict. Only cells that are produced in a pharmaceutical manufacturing process, the so-called „good manufacturing practice“ – GMP for short – may be used in humans. Setting up this procedure is very demanding.“ The cells produced under GMP conditions are first used in animal models for the preclinical safety tests. The requirements of the regulatory authorities, in Germany the Paul Ehrlich Institute, demand that only laboratories specially accredited for this purpose are allowed to carry out the animal experiments for a clinical trial. The technical term is „good laboratory practice“ – GLP conditions. In their search for a GLP laboratory that also had microsurgical capabilities to transfer the muscle stem cells into the bladder sphincter of rats, the researchers found what they were looking for in the USA: „About 300 kilometres east of Chicago, in the middle of Michigan, there was such a laboratory,“ reports Prof. Spuler. „In order to explain to our colleagues there exactly what we were planning, we had to travel to the USA several times. The preparations, the necessary training period and the execution of the experiments were incredibly time-consuming and costly. We couldn’t have done that without the support of the BIH-Spark programme!“
BIH provided one million euros to Prof. Spuler’s research team. „This is exactly our concern,“ explains Prof. Dr. Christopher Baum, Chairman of the BIH Board of Directors and Board Member for Translational Research at Charité. „We want to support scientists in bringing their results from the laboratory to patients and thus promote medical translation. In this way, we achieve that research becomes health.“ Dr Tanja Rosenmund, the head of the BIH-Spark programme is also pleased. „The project for epispadias is so exciting because – if it succeeds – it opens up many other possibilities: After all, incontinence is a widespread problem and muscle weakness anyway. We therefore hope that this funding will pave the way for as many further studies as possible.“
After the results in the USA showed that the transplanted muscle stem cells were able to remedy the incontinence in the rats and that the safety of the cell product could be confirmed in the best possible way, there is now nothing standing in the way of the clinical trial: 21 affected boys between the ages of three and seventeen are to be treated at the university hospitals in Ulm and Regensburg. There, Prof. Dr. Anne-Karoline Ebert and Prof. Dr. Wolfgang Rösch head centres for paediatric urology. The study is planned to be placebo-controlled, randomised and double-blind. This means that randomly selected five of the 21 boys will receive a placebo (saline solution) instead of their own muscle stem cells. Neither treatment providers nor patients know who these five were until the end of the study. „We have to do this to get scientifically validated results,“ explains Prof. Spuler. „If, after the data analysis, it turns out that the children are better off after the cell injection than those who received the placebo, there is, of course, the possibility to follow up with the cell injection. This is possible because the isolated muscle stem cells can easily be kept frozen.“ The first patient should be treated in a few months.
About the Charité – Universitätsmedizin Berlin
The Charité – Universitätsmedizin Berlin is one of the largest university hospitals in Europe with around 100 clinics and institutes on 4 campuses and 3,001 beds. Research, teaching and patient care are closely interlinked here. With around 16,391 employees across Charité and 19,400 across the group from over 100 nations, Berlin University Medicine is one of the largest employers in the capital. Of these, 4,707 were employed in the nursing sector and 4,693 in the scientific and medical sector. Last year, 132,383 full and partial inpatient cases and 655,138 outpatient cases were treated at Charité. In 2020, Charité generated total revenues of around 2.2 billion euros, including third-party funding revenues and investment grants. With the 196 million euros in third-party funds raised, Charité achieved another record. At the medical faculty, which is one of the largest in Germany, more than 8,600 students are trained in human medicine, dentistry as well as health sciences. In addition, there are 577 training places in 10 health professions. The Berlin University Medical Centre focuses on the following research areas: Infection, Inflammation and Immunity including research on COVID-19, Cardiovascular Research and Metabolism, Neurosciences, Oncology, Regenerative Therapies as well as Rare Diseases and Genetics. Scientists at Charité work, among other things, in 28 DFG Collaborative Research Centres, including six with a spokesperson function, in three Clusters of Excellence, one of which has a spokesperson function, 9 Emmy Noether junior research groups, 14 grants from the European Research Council and 9 European collaborative projects with Charité coordination. Research at the Charité