BPAN

Since BPAN was only discovered in 2012, medical research is still in its infancy. So far, only individual side effects such as epilepsy or low muscles tone can be treated symptomatically. Proven drugs and therapeutic treatments are the means of choice. Treatment of the disease itself – both symptomatically and causally – or even a cure is not yet in sight.

Publicly funded research projects

Medical research is currently focusing on the more common variants of NBIA, mostly PKAN. Some aspects of this research also benefit the investigation of BPAN. In 2012, for example, the international TIRCON project at the LMU Munich under the leadership of Prof. Dr. med. Thomas Klopstock received EU funding. An important aspect of this project is the establishment of an international patient register together with a biobank. Particularly in the case of rare diseases, it is important to precisely document the course of the disease in so called natural history studies. The biobank serves to link this information with the genetic mutations and provides samples for lab work. The people affected by BPAN all have slightly different genetic defects. It is only through this database that research programmes can be planned and the efficacy of drugs to be tested better assessed.

Within the framework of TIRCON and other research programmes, an already available active substance called Deferiprone (Ferriprox) was tested on PKAN patients. It was investigated whether its ability to remove iron from the body also counteracts deposits in the brain. The first results show that it is possible to successfully remove excess iron from the brain cells. However, this does not seem to have a significant effect on the patients’ state of health.

EU funding for the TIRCON project ended in 2015. However, the patient register and biobank will continue and be expanded by means of other financing provided by the NBIA Alliance.

In Munich, other scientists such as Dr. Arcangela Iuso from the Technical University of Munich contributied to research into BPAN.

Prof. Dr. Tassula Proikas-Cezanne from the Department of Molecular Biology at the University of Tübingen has made important contributions to the research on BPAN. She has discovered the WDR45 gene and gained important insights into the function of the WIPI4 protein encoded by it. On 29th November 2019, the Collaborative Research Programme (SFB) 1177 “Molecular and Functional Characterisation of Selective Autophagy” funded by the German Research Foundation (DFG) was extended for another four years. The research programme is endowed with more than 12 million euros. Within the subproject E03 “Molecular functions of WDR45/WlPI4 in ferritinophagy and neurodegeneration” under the direction of Prof. Dr. Tassula Proikas-Cezanne, the WIPI4 protein and its role for BPAN will be investigated in more detail.

It is now assumed that the protein plays an important role in the process of autophagy. This process takes place in all body cells and can be described simply as the recycling in the cells. Since research into treatment options for more frequent neurodegenerative diseases such as Alzheimer’s, ALS or Parkinson’s has been largely unsuccessful, a malfunction of autophagy is also regarded as a decisive factor in these diseases. WIPI4 appears to have a crucial function in the formation of the autophagosome. These are cell organelles that collect cell material to be degraded.

Another centre for NBIA/BPAN research in Germany is the Institute for Neurogenetics at the University of Lübeck under the direction of Prof. Dr. med. Christine Klein. The focus here is on research into the relationship between genetic defects and impaired cell functions.

The Oregon Health & Science University in Portland, Oregon, USA has proven to be one of the most important and active research institutions in the field of NBIA and BPAN. The medical doctors Dr. Susan J. Hayflick and Dr. Allison Gregory are particularly noteworthy here. The researchers are currently working on various NBIA clinical trials and the development of a BPAN mouse model.

Research project funded by donations

In addition, however, there are hardly any publicly funded research programmes. Medical research on BPAN depends on donor-funded scholarships, which are currently awarded predominantly by the various patient advocacy associations, in particular the US based NBIA Disorders Association. Within this framework, a total of US$ 95,507 was awarded to the University of Pennsylvania for a follow-up study of BPAN patients in 2016 and 2017. A further US$ 50,507 was awarded in 2017 to Prof. Hong Zhang of the University of Massachusetts Medical School for his research work on autophagy (the utilisation of waste products in body cells). At the beginning of 2019, this research work was awarded a follow-up grant of US$ 51,020. In 2018, two further scholarships of US$ 150,000 and US$ 45,000 were awarded. They go to Dr. Young-Ah Seo of the University of Michigan and Dr. Mario Mauthe of the University of Groningen. Both are concerned with the relationship between autophagy, iron deposition and the variations of the WDR45 gene. They hope to contribute to future therapies. In August 2019, Dr. Lena Burbulla from Northwestern University in Chicago, USA, was awarded a grant of € 65,000 for a period of 18 months. She will further investigate the relationship between the symptoms of BPAN and the disturbed iron balance in the brain cells.

Some researchers are also investigating whether existing drugs approved for the treatment of other diseases can also have a therapeutic effect in the case of BPAN and other NBIA variants. An example is the Spanish Braincure project. Dr. Apostolos Papandreou‘s research programme at University College London, GB, which has been funded with £230,000 for four years since 2016, pursues a similar approach. At the end of 2019 it was announced that Prof. Paul Lockhart from the Murdoch Children’s Research Institute in Victoria, Australia, will receive a scholarship of US$61,245 co-financing a similar study.

In February 2019, the NBIA DA announced that another scientist would be active in BPAN research. Robin Ketteler from University College London, UK, received a research grant of US$ 51,020. His field of research is the regulation of autophagy. In this video he explains his work in the laboratory. He leads the research group in which also Dr. Papandreou is active.

In recent years and months, however, the treatment of other rare diseases has shown some spectacular success through gene therapies. In particular, the CRISPR/Cas9 method, also known as gene scissors, has enabled medical research and the development of treatments to make unprecedented progress. Some pharmaceutical companies are now specialising in the development of orphan drugs. Even if such approaches for the treatment of BPAN are still a long way from being developed, BPAN is ideally suited for this. Typically, the genetic defect that triggers BPAN is a mis-coding of the WDR45 gene in only one place. In 2017, researchers developed a method with which individual building blocks of the genetic code can be exchanged without having to split up the genome. If this procedure can someday be used for medical purposes, we might be a big step closer to curing BPAN.

All this shows that several paths are currently being taken in medical research on BPAN. At the moment we are still at the very beginning of basic research. Although one can already roughly predict the direction in which research will develop and must continue to develop, it is above all the lack of funding that hampers progress.