NBIA NEWS & INFORMATION

Dr. Young Seo, an assistant professor of nutritional biochemistry at the University of Michigan’s School of Public Health in Ann Arbor, gives an update on her work which will be completed in August 2021.

October 2020

Ongoing BPAN research, funded by the NBIA Disorders Association, is producing new insights into iron accumulation and cell damage in individuals who have Beta-propeller protein-associated neurodegeneration.

BPAN is one of the most common NBIA disorders, which share a common characteristic of iron accumulation in the brain. Researchers are trying to understand what causes the iron to collect in BPAN and its impact on disease symptoms.

In September 2018, the NBIA Disorders Association awarded its first-ever early career grant for $150,000 to Dr. Young-Ah Seo, an assistant professor of nutritional biochemistry at the University of Michigan’s School of Public Health in Ann Arbor. The two-year grant was to end in August 2020 but will be extended 12 months because of a research pause during the COVID-19 pandemic.

Seo is investigating how a mutation in the WDR45 gene in BPAN individuals leads to iron accumulation and cellular damage. Her team was able to successfully generate a cell model of BPAN in which the WDR45 gene is deleted. This model showed significantly elevated iron levels, which suggests that the model mimics the condition seen in patients with BPAN.

Using this cell line, the team saw that the loss of WDR45 caused significant changes in the cellular pathways that regulate iron, which may underlie the reason iron accumulates in the brain of BPAN individuals. The team also found that the loss of WDR45 produces toxic reactive oxygen species, which are unstable molecules that can easily react and cause cell damage. This could contribute to the neurodegeneration seen in BPAN patients.

Taken together, the findings to date suggest that alterations in specific iron pathways increase total iron levels, promoting oxidative stress and cell damage in the BPAN cell model. Seo’s team is searching for molecular targets that can reduce iron levels in the cell model. Once the project is complete, it could point to potential therapies for BPAN.

 

October 2020

A research team in the Netherlands is making progress in its study of how mutations in the WDR45 gene affect beta-propeller protein-associated neurodegeneration (BPAN).

Dr. Mario Mauthe from the University of Groningen, Netherlands, received a $45,000 grant from the NBIA Disorders Association and this update is the results from that work.

The team is being led by Dr. Mario Mauthe of the University of Groningen, who in 2018 received a $45,000 grant from the NBIA Disorders Association and is updating us on the results from that work.

BPAN is one of the most common NBIA disorders, which share a common characteristic of iron accumulation in the brain. Researchers are trying to understand what causes the iron to collect in BPAN and its impact on disease symptoms.

The researchers first investigated whether a WDR45 mutation caused disruption in a cellular process known as autophagy, in which cells recycle damaged materials and get rid of waste. They wondered if that could explain the iron accumulation observed in the brains of BPAN patients.

The team observed that the absence of the WDR45 gene does not disrupt the natural process of autophagy but that cells carrying the mutation have defects in the mitochondria, which are the energy-producing compartments within a cell. Because other NBIA patients have mitochondrial defects, it could be common to multiple NBIA diseases.

Mauthe’s team is investigating whether or not the defective gene causes issues with autophagy specifically targeting mitochondria. More research is needed to sustain their hypothesis and to understand why this defect occurs and whether treating it would be a valuable avenue for future therapies.

 

Professor Robin Ketteler of University College London research update. Funds for the research grant were raised at the 2018 Million Dollar Bike Ride.

October 2020

Professor Robin Ketteler and his team at University College London have completed drug screening for potential BPAN therapies and identified several candidates that will advance to the next level of testing.

Ketteler’s team received a 2019 grant from the NBIA Disorders Association and recently reported the successful results. The BPAN drug-candidates can restore autophagy in BPAN cells, the natural process of cleaning up toxic damage in cells that is impaired in BPAN patients.

“Our results are a great starting point for further drug development,” says Ketteler. “These chemicals have characteristics of drugs, and they work in our neuronal cell model.”

The next steps are to ensure that these drug-like molecules also work in the more complex environment of the brain and can reach the brain regions that most need help.

To that end, the team plans to develop tissue models of BPAN using three-dimensional cell models.

Ketteler’s grant was made possible from funds raised by BPAN families for the 2018 Million Dollar Bike Ride held by the Orphan Disease Center at the University of Pennsylvania. Our organization writes the request for proposals and members of our Scientific & Medical Advisory Board review the applications. The University of Pennsylvania manages the grants and sends us copies of the scientific reports that are generated.

This work was done in collaboration with Professor Manju Kurian and Dr. Apostolos Papandreou, both from University College London. They had received a grant to study BPAN from our organization in 2014. (See article at https://www.nbiadisorders.org/images/newsletters/2018-apr-may-news.pdf, pg. 6).

Ketteler’s team built on the 2014 work, which produced a laboratory model of BPAN, using skin cells from BPAN patients and reprogramming those cells into neurons. Those cells were examined using state-of-the-art techniques to identify differences from cells in healthy people. The researchers learned that genes and proteins involved in iron metabolism are present in the patients’ cells at abnormal levels in comparison to healthy cells. This is in line with the disease’s characteristic buildup of iron in the brain. This finding encouraged the team to look more closely at the potential causes for such an increase in iron.

Ketteler is an expert in early stage drug discovery. “These findings are very exciting,” he said. “They present an opportunity to use our drug screening technologies to identify small molecule chemical compounds that might restore autophagy in these cells.”

Using innovative screening technologies involving sound to propel compounds onto the cells, Ketteler screened thousands of small molecule compounds for ones that might enhance autophagy in BPAN neurons. Interestingly, some of the compounds are part of a collection of FDA-approved drugs already being used for other diseases.

Ketteler is seeking additional funding to continue this research.