NBIA NEWS & INFORMATION

BPAN families have a new way to share data, accelerate research

- By Patricia Wood

RareX logoJune 2021

BPAN individuals and families are invited to share health information about the disorder on a new, secure platform so that researchers will have access to far more information than would otherwise be possible.

Launched Aug. 6, the RARE-X BPAN Federated Data Platform is designed to encourage data-sharing  and, thus, quicken the spread of information and the pace of research into BPAN. The platform is free for families to use. Importantly, it keeps health information confidential by providing only data that is not attached to individual names. Individuals and families affected by Beta-propeller Protein-Associated Neurodegeneration (BPAN), believed to be the most common NBIA disorder, control whether to allow or deny access to their personal health information for any research project.

RareX PrinciplesRARE-X BPAN asks BPAN families about their experiences with the condition through various structured and standardized surveys on various topics which can be updated by families as needed. A researcher who is studying mitochondria, for example, can do a query for all relevant information on a specific symptom and might find similarities across various diseases that provide insights and new treatment pathways.

The platform is currently open to BPAN families who speak English. Those wishing to participate  can access the site at https://bpan.rare-x.org. Translation services are not yet available, but RARE-X hopes to provide this feature in the coming year. It also plans to add more rare disorders as time goes on.

Our community has gotten in on the ground floor with RARE-X, a newly formed nonprofit, along with five other organizations that represent individuals with BPAN: Hoffnungsbaum e. V. in Germany, Stichting Ijzersterk in the Netherlands, and three BPAN-only focused organizations: BPAN Warriors in the U.S., BPAN France, and Autour du BPAN, also in France.

Rare-X was created by leaders in the fields of patient advocacy, medical research, biopharma and technology. The founder and executive director of the nonprofit is Nicole Boice who founded Global Genes.

Megan O’Boyle, patient engagement lead at RARE-X, spoke at our May family conference about the program (you can see the video here). It has closed captions enabled and can be watched in multiple languages. We are hopeful that other NBIA disorders can be added to the platform in the future.

The initiative is powered by some of the great leaders in rare disease and supported through partnerships with the Broad Institute and Harvard University. In addition, expertise is provided by the National Institutes of Health,  private and commercial enterprises, academia and rare patient advocacy groups.

RARE-X provides support, technology, tools and resources necessary for successful data collection, and secure but open data sharing on a global scale. The organizers believe that by removing barriers to access and analysis, diagnosis, and disease understanding, the development of therapies for rare disorders can be accelerated.

This platform does not replace other forms of data collection that we have available in our NBIA community with BPANready, Citizen and the TIRCON International NBIA Registry & Biobank. In fact, these existing projects can be connected to the RARE-X platform and expand the data available to interested researchers.

We believe RARE-X BPAN enhances our readiness for clinical trials and engages new researchers and biotech companies. It is cloud-based and researchers can query the database in myriad ways to find data that is brought together rather than in separate silos. The de-identified data never leaves the system. Researchers can link to it but cannot download it.

We are excited about this resource and its potential to lead to faster treatments and cures.

 

Study brings new insights on BPAN defective gene

Dr. Lena F. Burbulla 

Dr. Lena F. Burbulla, of the Biomedical Center
at Ludwig-Maximilians-University in Munich,
received a 2019 BPAN research grant funded by
AISNAF in Italy, Hoffnungsbaum e.V., in Germany,
and the NBIA Disorders Association

June 2021

A recent study of Beta-propeller Protein-Associated Neurodegeneration (BPAN) gained promising preliminary insights in how the defective BPAN gene may cause breakdowns in the cell clean-up process as well as iron accumulation.

BPAN is now believed to be the most common of the NBIA disorders.

The research on the mutated BPAN gene, WDR45, was led by Dr. Lena Burbulla who was working at Northwestern University in Chicago at that time. She received a 2019 grant for 65,000 euros, equal to about $73,000.

The grant was funded by AISNAF in Italy, Hoffnungsbaum e.V., in Germany, and the NBIA Disorders Association. AISNAF managed the grant.

The WDR45 gene is involved in autophagy, a mechanism by which unneeded components of the cells are broken down and recycled. To date, it is not clear how the mutated gene leads to the brain iron accumulation, along with all of the disease features observed in patients with BPAN.

In the study, Burbulla first generated neurons from induced pluripotent stem cells (iPSCs) derived from small flaps of patients' skin. She examined the neurons’ autophagy process, which ultimately leads to the breakdown of proteins in the lysosomes. Lysosomes are organelles, i.e. "small organs" within a cell, and are mainly involved in collecting cell waste and transporting it outside the cell. The lysosomes in BPAN neurons probably have defects and are only able to dispose of proteins and cell organelles to a limited extent. This could also affect iron-binding proteins, among other things.

If confirmed in further studies, it could be a possible explanation for the pathological accumulation of iron observed in the neurons of BPAN patients. When examining the neurons, an accumulation of neuromelanin was also found, which may be due to poor iron regulation. Neuromelanin is, in fact, one of the molecules that can bind iron and typically is present in dopaminergic neurons — the neurons most affected in BPAN.

Another project goal was to create more sophisticated models of the disease. Using the pluripotent stem cells of patients, Burbulla was able to create three-dimensional cellular structures that, although much simpler than the human brain, allowed her to mimic and study the pathology in a system similar to a small brain. Analysis has confirmed that mini-brains contain structures typical of regions of the brain affected by BPAN, and have shown defects similar to those observed in simpler cell models, such as decreased lysosomal enzymes and neuromelanin accumulation.

The project’s third objective was to explore therapeutic strategies. Preliminary results using antioxidant molecules showed a partial improvement in defects in the models. Ultimately, the findings, while preliminary, opens up new and interesting perspectives on the functions of the WDR45 gene.

Burbulla recently moved to the Biomedical Center at Ludwig-Maximilians-University in Munich, where she heads the "oxDOPAMINE" project funded by the European Research Council as part of the SyNergy Cluster of

Excellence. In this project, she will investigate why nerve cells in the midbrain are susceptible to an accumulation of the oxidized neurotransmitter dopamine and subsequently degenerate. Because she suspects that in addition to a defective dopamine metabolism a disturbed iron balance also plays a critical role, she wants to focus on rarer neurodegenerative diseases in addition to the relatively common Parkinson's disease. BPAN research will be included in her work.

 

CoA Therapeutics launches phase 1 PKAN drug study

CoA logoJune 2021

CoA Therapeutics Inc., in April began a phase 1 study of the safety of a potential drug for Pantothenate Kinase-Associated Neurodegeneration (PKAN) by testing it in healthy volunteers.

The CoA Therapeutics team plans to begin clinical trials in PKAN patients in late 2022, once it is determined that the drug candidate they are calling BBP-671 is safe and a suitable dose for PKAN patients has been determined.

PKAN is one of the most common NBIA disorders.

The necessary preclinical animal studies with BBP-671 have been completed, and the Food and Drug Administration has approved the company’s application for the use of the Investigational New Drug in humans. Orphan drug designation has also been granted in both the US and Europe.

The patented compound changes the action of pantothenate, a key enzyme involved in metabolism, as it’s converted into CoA. CoA is deficient in PKAN individuals. The drug is a unique synthetic molecule that can immediately relieve  the movement disorder and extend the life span in a mouse model with brain CoA deficiency. It compensates for the missing CoA, and the company hopes it will have a similar affect in PKAN individuals.

 

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