During the conference on autophagy in Tübingen in September, Markus was invited by Prof. Christian Behl, head of the Institute of Pathobiochemistry at the University of Mainz, to a workshop in New York on 24 October 2019.
This meeting, entitled “Alzheimer’s, Related Disorders and Autophagy“, brought together for the first time outstanding scientists from Germany and the USA in the fields of the most common neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s and ALS to discuss the differences and similarities of these syndromes. In particular, the cellular process of autophagy was targeted, which is likely to play a major role in many of these diseases.
This rather new approach has been adopted because, even after many years of research, attempts to combat these diseases have been largely unsuccessful. Another reason is that there are often already findings on certain aspects of a disease that have been obtained in other research fields and of which researchers from neighbouring disciplines know very little. This is certainly also true for NBIA and BPAN, if one looks at research on other neurodegenerative diseases and autophagy.
Mr Behl had invited Markus to talk about a neurodegenerative disease that is not caused by age but by a genetic defect. Among the NBIA variants, there are some in which autophagy is defective. These include, for example, BPAN. MPAN is also thought to be related to autophagy. As the father of a daughter with BPAN, this was of course a great opportunity to learn new things about current research progress, but also to make new contacts. So it happened that Markus met Sarah Chisholm, mother of a daughter with BPAN and an energetic activist who founded the initiative “BPAN Warriors” in the USA.
The one-day workshop consisted of 14 lectures and plenty of room for discussion. As was to be expected, Markus did not understand everything by far, but he was able to pick up some interesting details for Milly’s Mission, Hoffnungsbaum and NBIA. So there is a mitophagy as well as an autophagy. While autophagy generally identifies and captures functionless and harmful cell fragments, mitophagy focuses on mitochondria, i.e. the power plants of cells. Special receptors differentiate between defective and healthy mitochondria. Both processes take place in different areas of the brain cells.
It has also been mentioned that a malfunction of autophagy can lead to an excess of calcium in the brain cells. This makes them more sensitive to electrical stimuli, which could be a cause of epilepsy. In lab tests, calcium blockers have been shown to normalize the irritability of these cells.
One result was particularly exciting because genetic mutations seem to lead to so-called crosstalk to other body functions beyond the processes directly controlled by the gene and the disease syndromes. There are clear indications that the sense of smell is altered in connection with a disturbed autophagy – at least in nematodes. Other impairments are not excluded.
Some lectures dealt with clinical applications and studies. Studies on the treatment of Alzheimer’s disease also failed because the previously defined success criteria (clinical endpoints) were not met. An important lesson from these trials is to start with early forms of the disease and to include as many subgroups as possible in the study. A meaningful patient register with as many cases as possible is essential for this. This also applies to NBIA diseases, for which there is already an international NBIA patient register.
With a short lecture Markus could finally point out the work for Millys Mission and Hoffnungsbaum e.V. as well as present NBIA and BPAN. This contribution met with great interest. Afterwards several participants approached him and gave tips for helpful contacts or strategies for the development of therapies.
The workshop closed with a 90-minute public event. In addition to three presentations that were easy to understand, it consisted of a panel discussion in which Markus was the only representative of a patient organisation to participate. The discussion was divided into a moderated section with concrete questions and a public round of questions. Here Markus could obviously impressively describe the necessity of patient organizations such as Hoffnungsbaum as well as the course of BPAN. Prof. Behl confirmed that his contribution had been very important. Our contact will continue in the future.
Overall, the short trip to New York was successful. Markus was able to gain many new impressions about details of autophagy and to generate some interesting contacts, which will certainly also be of interest in the future.
On 24 September 2019, Markus participated in a public panel discussion on “Autophagy and its importance for health and neurodegeneration”. It took place as part of this year’s Fall Conference of the Society for Biochemistry and Molecular Biology (GBM) and the German Society for Cell Biology (DGZ) in Tübingen. Markus attended as a representative of Hoffnungsbaum e.V. and presented “Millys Mission” to the participants.
All images by Noah Rusch
The host and autophagy researcher Prof. Dr. Tassula Proikas-Cezanne had invited him for this discussion in order to represent for Hoffnungsbaum neurodegenerative diseases that already begin in childhood. Autophagy is disrupted in some NBIA variants, including BPAN. It is a cellular process that is responsible for the degradation and recycling of substances that are produced as waste materials during metabolism and cannot be used by cells. Autophagy ensures that these substances decompose and can be made available to the cell again as building blocks. It plays an important role in age-related diseases such as Alzheimer’s and Parkinson’s disease.
Three renowned scientists took part in the discussion: Prof. Proikas-Cezanne, Prof. Dr. Christian Behl (Director of the Institute of Pathobiochemistry at the University of Mainz) and Prof. Dr. Frank Madeo (Head of the “Ageing and Cell Death” working group at the University of Graz). The Lord Mayor of Tübingen, Boris Palmer, joined the group. The discussion was chaired by the well-known science journalist Ina Knobloch.
The one-hour discussion highlighted both the topic complex “autophagy” as a health-relevant mechanism in old age and its disruption due to congenital genetic mutations, here shown with the example of BPAN. Markus had the opportunity to give an impressive account of how BPAN affects the lives of children and what challenges this disease poses for the affected families. This information is particularly interesting and motivational for researchers, since genetic diseases associated with autophagy are not well known.
Prof. Proikas-Cezanne is particularly interested in decoding BPAN. She discovered the WDR45 gene more than 15 years ago. The causal role of this gene for a NBIA disease, which then received the name BPAN, was first described in 2012 by scientists of the TIRCON consortium. Prof. Proikas-Cezanne also extensively studied WIPI4, a protein whose function was impaired by BPAN mutations, and revealed its role in autophagy.
This is the beginning of what may be a long-standing partnership in the fight against BPAN. Prof. Proikas-Cezanne has already initiated a BPAN research project with public funds. We will inform you as soon as we know more about it.
On 21 June 2019 we could welcome at our home Prof. Dr. Tassula Proikas-Cezanne. She is a molecular biologist at the University of Tübingen, Germany. The scientist discovered the WDR45 gene and established the connection between the WIPI4 protein and autophagy. She is currently investigating the importance of this protein for autophagy. Therefore, she is researching an important mechanism that is probably responsible for BPAN. Prof. Proikas-Cezanne is very interested in cooperating with Hoffnungsbaum e.V..
From 26 to 27 September 2018 Milly’s mother took part in the annual meeting of the German Corporation for Gene Therapy (DG-GT) in Freiburg im Breisgau. She caught up on new developments in gene therapy, especially on CRISPR/Cas, the so-called gene scissors. Technical opportunities in this area develop rapidly. Even rare neurodegenerative diseases are supposed to become more and more treatable in future. But is gene therapy even eligible for our BPAN-kids? She discussed this question with the outgoing president of DG-GT Cristof von Kalle. He did not only answer all her questions patiently and in detail but he even introduced her to her some people who could give a new impetus to our movement.
Concerning BPAN nothing specific could be discussed. However, this was to be expected as the disease has to be decoded first. Nevertheless, it is very useful to get used to the possibilities given by CRISPR/Cas etc. in order to use every chance and to decide whether these medical technologies can be used for treating BPAN. At the moment, we are summing up the results of the discussion for the BPAN-FB group who are already very excited to learn about them. At this point, a heartfelt thank-you to Cristof von Kalle for having supported our BPAN team with advice and tips!
From 21 to 22 September 2018, we were participants in the 8th NBIA Family Meeting Germany organised by Hoffnungsbaum e.V. and which took place in Düsseldorf. NBIA – Where are we in research and treatment? was the meeting’s main topic. About 75 participants from Germany and abroad arrived. The presentations were very interesting and entertaining.
Thomas Klopstock (Friedrich Baur Institute, Munich) gave an overview on the state of research on PKAN and the other types of NBIA. Ivan Karin (Friedrich Baur Institute, Munich) examined similarities as well as differences among the NBIA diseases. The international NBIA patient registry was presented by Boriana Büchner (Friedrich Baur Institute, Munich). The fact that only 16 BPAN patients have enrolled in the registry so far was irritating for the BPAN patients’ relatives. The registry is fundamental for the research and the understanding of BPAN. It cannot be stressed often enough how important the enrolment in the registry is, see also our entry from 6 April 2018. Matias Wagner (Helmholtz centre, Institute for neuro genomics, Munich) gave a lecture on genetic counselling concerning NBIA diseases. That this is a topic bothering all NBIA patients’ relatives became clear straight away. Unfortunately, the time was not sufficient to answer all questions.
Milly’s father, then, spoke about life with a child suffering from NBIA, taking Emilia as an example and he presented Milly’s Mission. The presentation given by Kristina Müller (Neuropediatric therapeutic clinic St. Mauritius, Meerbusch) was very interesting. She described her active work in rehab for neurodegenerative diseases in childhood and adolescence very impressively.
Thomas Kmiec (Children’s Memorial Health Institute, Warsaw) focused on the medical treatment of MPAN in his presentation. Ody Sibon (UMC Groningen) reported about the journey from basic research to clinical studies and Arcangela Iuso (TU Munich) presented the bio bank and NBIA projects for MPAN and BPAN at the TUM. Agnés Rötig’s (University Paris Descartes) presentation about the similar disease mechanisms for all NBIA types was followed with great interest.
On Saturday, we got to know NBIA Suisse and NBIA Iran. Both associations were founded by Fatemeh Mollet, the aunt of three young women in Iran suffering from MPAN, living in Switzerland. Both associations focus on the applied research of NBIA. Thanks to its great commitment the association was able to realise two perennial research projects on MPAN. Moreover, the association’s chairperson, Angelika Klucken, presented the NBIA Alliance.
The event was very successful. For Markus, Milly and me it was the first NBIA conference and we were very happy to finally get to know so many concerned families and scientists in person. Concerning BPAN it was important for us to know that even NBIA types that have been neglected in research so far are now more and more coming to the fore. Over the last months, some BPAN research fellowships have been tendered and we are excited to find out who is going to carry out the research on BPAN and on which topic.
Subsequent to the conference the association’s general meeting including the new board’s election took place. Milly’s father was elected board member and vice chairman of Hoffnungsbaum e.V. Furthermore, Milly’s Mission 2017/2018 contributed the highest amount to the association’s donation volume which makes us very proud.
On 6 April 2018, Milly’s data were included into the TIRCON patient registry and the biobank. TIRCON is an international project at the Friedrich Baur institute of the LMU Munich under the leadership of Prof. Dr. med. Thomas Klopstock financed in 2012 thanks to EU funding. An important aspect of this project is the establishment of an international patient registry along with a biobank. Especially for rare diseases it is of high importance to exactly document the progressive forms. The biobank is supposed to connect this information with the genetic mutations. Even the persons affected by BPAN suffer from slightly different gene defects. Only with this database research can programs be planned and the efficiency of medications to be tested be better evaluated. The institute practises NBIA basic research. The results are the precondition for the development of a medication or a therapy strategy against BPAN. We therefore cannot emphasize often enough how important the inclusion of all BPAN patients into the TIRCON patient registry is!
We, relatives of BPAN patients, cannot do a lot. Providing the scientists with important data concerning BPAN by participating in TIRCON is a must and absolutely essential. If you are a relative, an acquaintance or a friend of a BPAN patient please do not hesitate to point out the possibility of participation in TIRCON to him/her or his/her care family! Beforehand, the institute has to be provided with all medical findings. The process of registering takes about three hours. Lots of questions regarding Milly’s progression of the disease and her development were asked. Moreover, information about the family tree and previous diseases of the parents are necessary. Milly was then examined. Finally, all of us had to provide blood and urine for subsequent analyses. Should you have any further questions we are happy to answer them.
On 22 March 2018 Markus took part in NRW’s fundraising day in Gelsenkirchen as a representative of Hoffnungsbaum e.V. In the following weeks and months, the topic of fundraising is going to be a central component of Milly’s Mission to combat BPAN.
On 20 February 2018. Milly’s mother participated in the symposium of the Eva Luise and Horst Köhler Foundation for people affected by rare diseases. This was our start into this year’s Rare Disease Day. New therapies – high hopes and open questions was the interdisciplinary symposium’s topic regarding rare diseases that took place in Milly’s hometown, Heidelberg, for the first time. Unfortunately, NBIA and BPAN were not addressed. The event, however, was very interesting and successful.
Prof. Cristof von Kalle informed us on gene therapy’s principles and raised hopes on our side that even therapeutic treatment for rare neurodegenerative diseases might be realized someday. E.g. Prof. Jan Kirschner reported about a fantastic break-through in research. The developed anti-sense therapy makes it possible to stop the severe and deadly progression of spinal muscular atrophy type 1.
Dr. Angela Schulz presented wonderful and encouraging studies’ results regarding the enzyme replacement therapy for NCL2 patients. The so-called “children’s dementia” that had previously progressed rapidly and had always been deadly could be stopped in 90% of the cases participating in the study. However, you cannot consider it as a cure for those two cases.
Nevertheless, it was repeatedly mentioned that more could be done and that one could treat more quickly if health policy decisions were taken faster and if there were urgently needed research funds available for rare diseases. As “Research …”, according to Eva Luise Köhler’s welcoming address, “… is our sharpest sword”. It was also stressed that it is fundamental to find out as much about disease mechanisms for rare diseases as possible for the development of therapeutic treatment.
At the end of the symposium we felt strengthened in our work: Milly’s Mission can succeed! Nevertheless, we have to fight even more energetically and we have to start at different points: not only fundraising and attracting attention but also involving more relatives of concerned BPAN patients, winning capable experts for our movement, being uncomfortable, reaching out to political decision-makers. We still have got a long way to go.