NBIA NEWS & INFORMATION

- By Patricia Wood

June 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.

RARE-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.

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.

June 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.

April 2021

June 12 marks the eighth annual Million Dollar Bike Ride and the second year it will be virtual because of the COVID-19 pandemic. If Team NBIA Disorders raises at least $20,000, every dollar will be matched, up to $30,000, to support a grant for BPAN research.

This is the fifth year Team NBIA is raising money to support new discoveries in BPAN, and anyone can take part — with as much or as little exertion as desired. Last year’s ride resulted in a $71,471 BPAN grant award.

The ride is organized by the University of Pennsylvania’s Penn Medicine Orphan Disease Center, and participants can cycle in their own neighborhood or even their living room. Others can support the team by spreading the word. Registration for riders is available at https://www.milliondollarbikeride.org/registration.

Choose Neurodegeneration with Brain Iron Accumulation when registering to be connected to Team NBIA Disorders. 

With the fundraising period heating up, anyone wanting to take part can register for $25 to join Team NBIA Disorders to cycle and raise donations by creating your own MDBR page with a link to send to friends and family to donate to your page. Those who don’t wish to create a fundraising page can register for $45, with the money going to Team NBIA Disorders as a donation toward the fundraising goal and then can participate in all the weekly challenges and cycling events.

Weekly challenges and classes for riders are in the works now. A virtual presentation is planned, along with a live spin class on June 12 at 11 a.m. EDT with pro  cyclist Nikki Theimann. As an added incentive, cyclists will be receiving goody bags this year.

Individuals who want to help but don’t want to register to ride can post  information about donating on social media or by sending an email to friends and family requesting their support for Team NBIA Disorders page at http://givingpages.upenn.edu/CureNBIA. Our team has made the match the last four years we’ve participated, and with your help, we will succeed again this year.

For more information, pictures and a video on Team NBIA Disorders and the  Million Dollar Bike Ride see https://www.nbiadisorders.org/mdbr-2021.

Left to right: Drs. Lara Barazzuol, Mario Mauthe, Muriel Mari and Fulvio Reggiori
from University Medical Center Groningen in The Netherlands.

April 2021

A BPAN research grant that could inspire new approaches to treating the disorder was awarded in January through the University of Pennsylvania with collaboration from the NBIA Disorders Association.

The grant went to Drs. Fulvio Reggiori, Mario Mauthe, Muriel Mari and Lara Barazzuol from University Medical Center Groningen (UMCG) in The Netherlands. Their research project is titled “Deciphering the causes of mitochondrial network disruption in WDR45-defective cells and their contribution to the BPAN pathology.” It is designed to determine how gene mutations contribute to Beta-propeller Protein-Associated Neurodegeneration (BPAN), the most prevalent of the NBIA disorders.

Funds for the one-year grant were raised through the virtual Million Dollar Bike Ride (MDBR) fundraiser held in June 2020. Families raised $35,000 and $30,000 of that was matched, dollar for dollar, by Penn’s Orphan Disease Center. When combined with registration costs and additional sponsor funds, the research grant totaled $71,471.

This is the fourth time research supported by the NBIA Disorders Association qualified for Million Dollar Bike Ride grants. Our organization writes the request for proposals, and members of our Scientific & Medical Advisory Board review grant applications. The University of Pennsylvania manages the grants and sends us a copy of the final scientific report grant that recipients will provide. Selection is based on the grant proposal’s relevance, feasibility and scientific merit.

The WDR45 gene, which when mutated causes BPAN, produces a protein called WDR45 that appears to be involved in autophagy, the process in which the body’s cells clean out damaged or unnecessary components. However, the precise molecular function and contribution of this protein to this pathway remains unclear.

This research will be taking a closer look at the mitochondria, which are the small structures in cells responsible for important processes such as producing energy, regulating metabolism, inflammation and cell death. Mitochondrial dysfunction is observed in genes mutated in certain NBIA subtypes, including the PANK2 gene in PKAN, the COASY gene in CoPAN, the PLA2G6 gene in PLAN and the C19orf12 gene in MPAN, carry instructions for mitochondrial proteins.

The team’s preliminary data reveals that cells with a WDR45 deficiency have a disorganized mitochondrial network. This indicates that WDR45 is also part of other cellular processes in addition to autophagy. The main goal of the research is to characterize how WDR45 deficiency leads to mitochondrial network disorganization and unveil the consequences of this to the cell.

The research will initially be performed in model cell lines followed by experiments using stem cells, a type called induced pluripotent stem cells (iPSCs). These iPSCs come from donated BPAN patient urine cells that are reprogrammed to become iPSCs. The IPSCs can then be reprogrammed in a lot of other human cell body cells, including the key brain cells affected by BPAN.

The team will search for metabolic pathways, which are a series of connected chemical reactions in the cell, that are affected in BPAN patients due to their dysfunctional mitochondria. This knowledge could offer the possibility of developing treatments to rebalance these metabolic alterations and decrease the devastating symptoms of BPAN and, potentially, other NBIA disorders.

The project will take advantage of the expertise of the four researchers, who are strategically located at the same department of the UMCG: autophagy (Fulvio Reggiori), ß-propeller proteins (Mario Mauthe), brain organoids technology (Lara Barazzuol) and electron microscopy approaches (Muriel Mari).

This project is also benefitting from an ongoing collaboration between the awarded groups, Prof. Marina de Tijssen, a clinician at the Movement Disorders Groningen, which is the Netherlands center of expertise for NBIA diseases, and the Dutch NBIA foundation Stichting Ijzersterk.  Tijssen and the patient organization have been instrumental in getting in touch with the patient families donating the urine samples to generate the iPSCs.