NBIA NEWS & INFORMATION

Global Collaboration Highlights Progress at First BPAN Research Roundtable

By Amber Denton

In early October, the NBIA Disorders Association hosted the first BPAN Research Roundtable, bringing together thirteen nonprofit organizations from around the world that are leading efforts to fund and advance research into Beta-propeller Protein-Associated Neurodegeneration (BPAN). Since its discovery in 2012, BPAN has grown to become the most common NBIA disorder.

As the BPAN landscape has evolved, many families affected by the disorder have founded additional nonprofit organizations dedicated to funding research. They are joined by our fellow international NBIA Alliance organizations which, similarly to our organization, also support research into all NBIA disorders.

The roundtable included representatives from thirteen global organizations:  NBIA Disorders Association (USA), Don't Forget Morgan Foundation (USA), Isabel's Chance (USA), Duets Across America (USA), Action for BPAN (UK), Hope for Hermione (UK), BPAN France (France), BPAN Spain (Spain), Hoffnungsbaum e.V. (Germany), AISNAF (Italy), NBIA Poland (Poland), Stichting Ijzersterk (Netherlands), and NBIA Suisse (Switzerland).

The purpose of the roundtable was to ensure all organizations were up-to-date on ongoing research efforts in order to avoid duplicating work and to identify areas requiring further focus. Most importantly, the meeting reinforced a shared commitment to a common goal: finding effective treatments and ultimately a cure for BPAN. Since 2012, the research community has made significant advancements in understanding the disease and the participating organizations were proud to share progress in several key research areas.

One focus was sharing the status of current patient registries and natural history studies, which are essential for understanding the full spectrum of BPAN’s impact. These efforts track disease progression over time and provide valuable insights into potential treatment options.

Other areas of research discussed included autophagy, mitochondrial dysfunction, ferroptosis and biomarker identification. Understanding the cellular mechanisms behind BPAN is critical for developing therapies that can address its symptoms and measure their effectiveness. The group also discussed the need for development of a small molecule and advancing gene therapy initiatives. Both of these approaches could directly address the genetic causes of BPAN, offering hope for targeted a treatment.

Additionally, discussions also focused on FDA-approved compounds that are actively being screened and further studied in animal models. The hope is to identify drugs that have already been approved for other medicinal purposes that could be used off-label to improve symptoms of BPAN.

The roundtable also highlighted progress in creating consensus guidelines for the medical community and establishing NBIA Centers of Excellence and BPAN-specific clinics. These efforts are vital for ensuring families receive high-quality, specialized care while advancing research into the disorder.

With research institutions worldwide investigating various aspects of BPAN, the importance of continued collaboration has never been clearer. As Christian Magnet of BPAN France emphasized, “Act together to do better faster.” By sharing information and ideas, organizations can align their efforts, maximize resources and ensure their work complements one another.

Looking ahead, the organizations involved in the roundtable are committed to maintaining momentum and staying closely connected. Regular meetings every six months will help ensure that research efforts remain focused on the areas with the greatest promise.

“It was such an inspiring session to be a part of as a newly registered charity. It’s really valuable to start relationships with others in the world on a very similar path, filled with even more hope that we can beat BPAN and provide our kids with a much better-than-predicted future,” said Kelly Sayers of Action for BPAN. This sentiment reflects the shared optimism of the organizations that collaboration will accelerate progress toward meaningful breakthroughs for BPAN families.

Christina Ftikas of Don’t Forget Morgan Foundation added, “Collaboration and research efforts across BPAN foundations will only help the community get to the finish line faster and hopefully lead to further development of a treatment for our beautiful children.” The importance of these joint efforts cannot be overstated as the BPAN community continues to move forward with hope and determination.

This ongoing collaboration highlights the strength and commitment of the BPAN community. Together, these efforts are bringing us closer to a time when effective treatments and a cure are within reach.

By: Amber Denton

It is with a heavy heart that we inform the community that CoA Therapeutics has decided to discontinue the clinical trial of BBP-671, the compound the company was developing as a potential treatment for Pantothenate Kinase-Associated Neurodegeneration (PKAN). This decision was made after studies showed they were unable to identify a clinical trial dose that adequately balanced safety (toxicity) and potential clinical benefit.

In March, we shared that CoA Therapeutics announced a delay in their PKAN clinical trial due to the need for additional laboratory studies on BBP-671 to determine critical dosing and safety information. A significant challenge identified during these additional studies was the wide variability of BBP-671 blood levels observed in humans. Individuals taking the same dose of BBP-671 showed vastly different blood concentrations of the drug. This inconsistency posed a significant risk in determining an appropriate and safe dose for PKAN patients.

Toxicology studies in animal models of PKAN helped to establish a specific safety limit, or target blood level, for BBP-671 that cannot be exceeded due to safety and FDA regulations. The target blood level needed for efficacy was shown to be dangerously close to the safety limit.

Despite multiple studies and efforts to control these large differences in human blood levels, the exact cause of these variations remains undetermined, making it impossible to predict individual responses to the drug. Some individuals may have exceeded the safety limit, while others might have fallen below the target level, resulting in no clinical benefit.

Originally discovered through research led by St. Jude Children's Research Hospital in Memphis, Tennessee, CoA Therapeutics will return ownership of BBP-671 and related compounds to St. Jude. All their research data will also be shared to support any future research.

We are immensely grateful for the long-standing partnership with CoA Therapeutics. Their dedication to the NBIA community will not be forgotten. We appreciate their passion and desire to find a treatment for our PKAN families, and the amount of empathy and determination demonstrated year after year on behalf of our families.

CoA Therapeutics has released a detailed official announcement that you can read here along with their heartfelt message to the community

By: Patricia Wood

July 2024

Photo credit: Jan Greune (LMU)

Professor Lena Burbulla, Ludwig Maximilian University, Munich, Germany

In November 2022, the NBIA Disorders Association, along with three sister organizations in Europe, awarded two Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) grants of $70,000 each. These one-year grants were awarded based on priorities set during an MPAN workshop that was part of an MPAN Landscape Analysis project also funded by these same organizations.

Prof. Lena Burbulla of the Ludwig Maximilian University of Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, recently completed their research under this funding and have both reported promising findings.

The funding was made possible through an international collaboration that included AISNAF in Italy, Hoffnungsbaum e.V. in Germany, and Stichting Ijersterk in The Netherlands.

Burbulla’s research involved human disease modeling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so, her lab used induced pluripotent stem cells (iPSCs) generated from the skin cells of people affected with MPAN.

Brains of MPAN patients show massive loss of nerve cells in specific regions, predominantly a region in the midbrain called the substantia nigra. Here, the loss of cells producing the neurotransmitter dopamine is substantial and anticipated to be responsible for the vast majority of clinical symptoms. Therefore, Burbulla’s team used stem cells from MPAN patients and converted them into midbrain-specific dopaminergic nerve cells — the type of cells that degenerate in the brains of individuals affected by MPAN — to identify mechanisms specifically affecting this vulnerable cell type.

They were able to remarkably recapitulate important aspects of the disease pathology found in patient brains making patient-derived dopaminergic nerve cells a valuable model to study disease-specific phenotypes in a dish.

They also observed an accumulation of alpha-synuclein, a presynaptic protein known to aggregate in the brains of MPAN patients, a signature of iron misregulation leading to iron overload as well as axonal swellings that have been observed in postmortem brain biopsies.

Unbiased proteomic studies revealed some key mitochondrial proteins to be dysregulated and multiple proteins related to neurotoxicity and activation of the brain’s immune response to be enhanced. This unique protein signature may give a first insight into why dopaminergic nerve cells in the brains of patients are specifically vulnerable and degenerate.

Burbulla states that one of the most promising advantages of human iPSCs is their utility as a patient-specific disease model, offering the opportunity to gain deeper insights into disease mechanisms and progression. In this study, they demonstrated that iPSC-derived MPAN patient nerve cells recapitulate aspects of human disease pathology and therefore serve as a valuable model to better understand the disease-specific mechanisms underlying loss of C19orf12 function.

Burbulla plans to publish their results and hopes to conduct further studies using patient-derived disease models to guide future rescue strategies in the hope of identifying new therapeutic approaches to combat MPAN.

Dr. Rajnish Bharadwaj, University of Rochester Medical Center, Rochester, New Jersey

Bharadwaj’s research used fruit fly models that have a gene called nazo whose human counterpart is C19orf12, the gene that causes MPAN in humans. Using these fruit flies, Bharadwaj showed that Nazo protein is required for the maintenance of lipid droplets, which are storage sites for triglycerides (fat). In its absence proteins involved in curbing the utilization of fat (by lipolysis) are diminished. The loss of the nazo gene has a significant impact on the lifespan and health of the fly.

Bharadwaj is working on gaining a deeper understanding of the alterations in lipid droplets in flies lacking the nazo gene. Interestingly, human C19orf12 protein is highly enriched in adipose (fat) tissue. Bharadwaj’s findings suggest that lipid abnormalities may contribute to neurodegeneration in humans.

Bharadwaj has already published a paper on his findings that can be found here in PLOS Genetics: Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis | PLOS Genetics

He plans to use the data accumulated with this grant to get NIH funding to carry the work forward. It is hoped that this study will provide the foundation for future investigations into the role of the human C19orf12 protein in NBIA.

The NBIA Disorders Association, along with its international NBIA Alliance partners, remains committed to advancing research that brings us closer to understanding and ultimately curing MPAN. As we celebrate these advancements of Burbulla and Bharadwaj, we look forward to further breakthroughs that will improve the lives of those affected by NBIA disorders.