Robin Ketteler (see picture), Professor of Translational Cell Biology at University College London (UCL), received a grant from the NBIA Disorders Association in 2019. He is an expert in the discovery of compounds with drug potential. His team used innovative screening technologies to test thousands of small molecule compounds to see which could restore autophagy in a BPAN neuronal cell model.

The BPAN cell model used had been developed by UCL colleagues Professor Manju Kurian and Dr. Apostolos Papandreou since 2014 in a precursor project also funded by the NBIA Disorders Association. Using state-of-the-art technical methods, they examined it to identify differences to healthy cells and found abnormal amounts of genes and proteins in the BPAN neurons that play a role in iron metabolism.

In collaboration with Kurian and Papandreou, Ketteler's research group has now been able to identify several molecules during drug screening that were able to improve autophagy and are now being considered for the next stage of testing. Some of these compounds have already been approved by the US Food and Drug Administration (FDA) as drugs for use in other diseases.

The next steps are to ensure that these molecules can also act in the more complex environment of the brain and reach the brain regions that need the most support. To this end, Ketteler's research group plans to develop tissue models of BPAN using three-dimensional cell models. Ketteler is currently seeking additional funding to continue this research.

A recently completed BPAN study led by Dr. Hong Zhang (pictured) has led to a new understanding of how a genetic defect causes BPAN and how it might be corrected. Zhang is a visiting professor at the University of Massachusetts Medical School and a researcher at the Institute of Biophysics at the Chinese Academy of Sciences in Beijing. He and his team are now working on a treatment strategy for BPAN based on the study results.

The project was sponsored by the NBIA Disorders Association and the University of Pennsylvania, which organizes an annual charity bike race for rare diseases and doubles the amount raised per patient organization. In 2017 and 2018, more than $102,000 was raised for BPAN research, which was awarded to Dr. Zhang. The first publications from the project are already available.

Zhang and his team also focused on identifying the causes of neuronal damage in BPAN. They identified a disruption of autophagy caused by a mutation in the WDR45 gene and protein. Zhang generated mouse models with a deactivated (knockout) or missing Wdr45 gene in the central nervous system. The team also studied a closely related gene, WDR45b, which causes another neurological disease associated with mental retardation. These mice performed poorly in learning and memory tests.

Zhang and his team made an important observation about the defective autophagy process. In normal cells, the waste products in the cell are wrapped in a small pouch called an autophagosome. The autophagosome then transports the waste through the cell to another pouch called the lysosome. There, the autophagosome fuses with the lysosome and the waste is then broken down and recycled.

However, in the nerve cells that lacked the WDR45 and WDR45b proteins, Zhang's team found that although the waste products were taken up by the autophagosomes, the autophagosomes were unable to connect with the lysosomes for unloading and recycling. To remedy this dysfunction, the researchers attempted to bypass the site of interference. They found that by inhibiting the modification of another protein, O-GlcNAcyclation of SNAP29, they were able to reverse the autophagy defects in cells with WDR45/45B mutation. Zhang believes that this finding shows a promising avenue for treatment.

The preparation of this summary was supported by translations from www.DeepL.com/Translator (free version) is supported.