Translation is very important for rare diseases as they tend not to be the main focus of interest. Nowadays, many patients with rare diseases join forces to form rare disease patient organisations, thus providing the patient numbers required for scientific research into the disease. We have large, well-characterised patient cohorts that fully and freely support our efforts to improve treatment. Here in Swabia in southern Germany, we have managed to establish patient groups for ALS and FTD. As far as Huntington's disease is concerned, Professor Landwehrmeyer has been instrumental in establishing a Huntington’s disease network involving virtually all patients worldwide.

What have the researchers from Ulm contributed to the understanding of these diseases?

First, we have developed new disease concepts, and based on these we have defined new forms of treatment. We are now implementing these concepts by establishing patient groups. Second, we have characterised the natural course of these diseases. This is a prerequisite for measuring treatment success, otherwise there is no way this can be done. Third, here in Ulm we have developed concrete therapeutic interventions – pharmacological and others – for all three disorders in animals and in cell cultures. And we have also defined the genetic basis that is key to developing therapeutic interventions.

The insights gained from basic research, our own and others, can be systematically transferred to the patient groups. More specifically, we want to develop new forms of application for medicines. We want to find out how genes can be switched off more effectively and how drugs can be made to cross the blood-brain barrier. We want to improve the transfer to humans of findings obtained with animals, usually rodents, and thus reduce the number of animal experiments.

As far as diagnoses are concerned, Huntington’s disease can be unequivocally detected with a genetic test. However, FTD, frontotemporal dementia, is still difficult to detect. Hardly anybody, including doctors, knows much about this disease. In the case of ALS, there is little diagnostic uncertainty. Well-founded expertise for diagnosing the disease is available in Ulm.

What is important to me is that the treatment of these diseases goes way beyond pharmacology. As far as diseases that badly effect a patient’s personality are concerned, it is also about supporting relatives. There are support groups for patients with these diseases. An FTD support group has just got off the ground. These support groups accompany our work and try to establish a social framework through which these patients can be integrated into society.

Which approaches are you looking to use to achieve translation?

The three diseases have a different genetic basis. Huntington’s disease is a monogenetic disease and has an autosomal dominant pattern of inheritance that follows Mendel’s laws. It can be diagnosed before the onset of symptoms. We also know from our own research that the defective gene (ed. note: huntingtin) has a toxic effect on the nervous system and the entire body. It is therefore logical to try to reduce the effect of this toxin. We’ve been trying to do this for a year and a half using antisense oligonucleotides¹, which can partially shut down the huntingtin gene. The only problem is that the huntingtin protein, whose structure has recently been characterised by Professor Stefan Kochanek in Ulm², is essential for the development of the body and specifically for the development of the nervous system. One therefore needs to be careful when targeting the huntingtin protein, especially as far as children and adolescents who are still growing and who in exceptional cases can develop this disease are concerned.

A simpler method can be used when the level of activity of a particular gene is too low, something that can be caused by so-called “loss of function” mutations. As such genes are typically autosomal recessive, it is sometimes possible to increase the activity level of the gene. We are managing to do this successfully in people with spinal muscular atrophy.

We want to develop these new methods further experimentally. This also includes developing new forms of application of the gene therapies. The problem is that the molecules are so big that they cannot cross the blood-brain barrier. However, innovative methods involving nanoparticles that make the blood-brain barrier more permeable have now become available and will in future render repeated surgical interventions, including for small children, unnecessary.

The scientific questions arising from these diseases have some parallels and some differences. One has to look at the diseases individually as well as focusing on the subtypes. Although Huntington's disease is a monogenic disease and treatment is therefore specifically focused on one gene, only up to 70 percent of the clinical picture is determined by the huntingtin gene alone. It is still not known whether the remaining 30 percent of clinical symptoms are determined by environmental factors or modifying genes.

As far as ALS is concerned, we have examined 500 families in Germany and found that the disease follows an autosomal mode of inheritance in only about five percent of patients. 20 genes are known to be involved, and five of these are responsible for around 60 percent of the disease. Monogenic factors therefore play a much less important role in ALS than in HD.

The situation for FTD is similar to that of ALS. However, it is likely that more FTD than ALS cases have genetic causes. Our research shows that the literature figures, i.e. that 50 percent of all FTD cases have a genetic, autosomal dominant cause, are grossly overestimated. Here in the south of Germany we have no more than 15 percent.

Yes, the only question is whether this is relevant for therapy. The sequencing of the human genome has reached its limits in terms of interpretation. But there are more pragmatic treatment approaches that are to a lesser degree based on genetic findings. Professor Heiko Braak, who has been working in this field for more than ten years, is well-known for revolutionising how researchers think about neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. He used molecular markers to describe the progression of the diseases. He also characterised the diseases in their preclinical phases and found that the first disease-related molecular changes surprisingly occur in the gastrointestinal tract.

This shows that diseases can be characterised without genetics. Professor Braak has shown that neurodegenerative diseases do not invade the brain like a tsunami. Quite the opposite; the diseases take an anatomically defined path through the brain. And if this really progresses in a stereotypical way, then there might be a way to interrupt this path. This is a therapeutic opportunity which we are also pursuing here in Ulm.

We've already come quite far. Here in Ulm, we have actually developed quite a lot that's new. I'd like to mention Professor Kassubek who works in the field of imaging and is an outstanding specialist in neurodegenerative disease biomarkers. He has found that imaging findings represent the best ALS biomarkers³ that have been found so far. Another outstanding researcher is Professor Otto, who has developed not one, but in fact several biomarkers for detecting the disease in blood and cerebrospinal fluid. We will carry out our future studies using the biomarkers that have been developed over the past few years in the hope that they will be able to predict a therapeutic response. If so, we may be able to conduct trials that take less time to complete and are therefore less costly.

One of our institute's fundamental objectives is faster screening of therapeutically active substances. We have biomarkers for all three diseases, now they need to be used. But this brings us back to the start of our conversation: actively supporting our patients and their families is of prime importance.

References:

1 BIOPRO Baden-Württemberg GmbH: Can the ticking Huntingtin clock be stopped? (article published on 2nd August 2016), URL: https://www.gesundheitsindustrie-bw.de/en/article/news/can-the-ticking-huntington-clock-be-stopped/ (as of 10th July 2018)

2 University of Ulm: Decoding the structure of the huntingtin protein (press release, 22nd February 2018), URL: https://www.uni-ulm.de/en/med/fakultaet/med-detailseiten/news-detail/article/die-entschluesselung-der-struktur-des-huntingtin-proteins-kopie-1/ (as of 10th July 2018).

3 Jan Kassubek, Hans-Peter Müller, Kelly Del Tredici, Johannes Brettschneider, Elmar H. Pinkhardt, Dorothée Lulé, Sarah Böhm, Heiko Braak, Albert C. Ludolph: Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain, Volume 137, Issue 6, 2014, p. 1733–1740.