NBIA NEWS & INFORMATION

BPAN Researcher Finds Compounds that Restore Mitochondrial Health

by Patricia Wood

 

 DrIuso
Dr. Arcangela Iuso, of Helmholtz Zentrum Munich, in Munich, Germany. Her BPAN research grant funded by NBIADA was titled, “Understanding the functional link between mutations in WDR45 and reduced respiratory chain complex I (RCCI) activity, and exploring cAMP modulation as a therapeutic approach.”

Most research on BPAN has focused on problems with autophagy, a process that helps cells clear out waste. But in a recently completed study supported by the NBIA Disorders Association, a team led by Dr. Arcangela Iuso at Helmholtz Zentrum Munich in Germany, took a new approach. They asked whether mutations in the WDR45 gene which lead to damaged mitochondria (the energy powerhouses of cells) might also play a role in how BPAN develops.

 

The team first spotted this mitochondrial defect in the brain tissue of a BPAN mouse model. It appeared to be linked to the malfunctioning of a key mitochondrial enzyme known as Respiratory chain Complex I (RCCI), a discovery that Iuso co-authored in a 2021 publication available here.

For this new research, Iuso’s team studied skin and brain cells from BPAN patients. The brain cells were made in the lab by first turning skin cells into stem cells, then guiding them to develop into two types of brain cells: support cells called astrocytes and nerve cells called neurons.

They found signs of mitochondrial problems in both skin cells and astrocytes — but not in neurons. This suggests neurons may have ways to protect themselves from the damage.

To test whether the mitochondrial issues could be fixed, three different compounds were applied to skin cells to see if they could potentially restore the mitochondrial enzyme activity of RCCI in a laboratory setting.

These compounds were forskolin, resveratrol and b2cAMP. Forskolin and resveratrol are natural compounds sold as supplements, while b2cAMP is a natural compound found in all cells as part of the body’s signaling mechanisms. It is not sold as a supplement or medication.

All three compounds helped, but b2cAMP and forskolin were especially effective, fully restoring mitochondrial function.

To advance this research, the team will conduct long-term studies on astrocytes to evaluate whether the positive effects of these compounds are sustained. Additionally, the focus will expand to explore other cellular defects associated with WDR45 mutations, such as autophagy dysfunction and ER stress, with the goal of understanding how these compounds may correct multiple aspects of BPAN pathophysiology.

The next phase will involve testing these compounds in the available BPAN mouse model to evaluate their therapeutic potential in vivo. This critical step will provide valuable insights for translating these findings into clinical applications.

The research team is currently seeking additional funding from government grants and philanthropic organizations to move this work forward which will open the door to potential new treatments focused on improving mitochondrial health.

Lighting the Path to PKAN Treatment

by Patricia Wood

 

 DrMamoun
Dr. Choukri Ben Mamoun, at Yale University, works on PKAN research in hopes of finding a treatment.

The NBIA Disorders Association, in collaboration with our sister NBIA organizations in Italy (AISNAF) and Germany (Hoffnungsbaum e.V.), funded Dr. Choukri Ben Mamoun’s PKAN research with a $115,000 grant that was recently completed.

 

The NBIA groups’ research grant to Ben Mamoun at Yale University was titled “A High-Throughput Screen for PKAN Reversing Agents.” The goal was to look for small molecules that might restore normal function in human cells that are deficient in the PANK2 gene, which is impaired in individuals with PKAN. The hope is that such a drug could restore neurological function.

The PANK2 gene encodes the pantothenate kinase enzyme, which is involved in several essential biochemical reactions in the body. A drug that restores normal metabolism in the absence of PANK2 could be effective in treating PKAN.

To identify such compounds, Ben Mamoun’s group developed a tool using luciferase, a glowing enzyme. They connected the instructions for making this glowing enzyme to the “on-off switches” (promoters) of genes involved in producing CoA. This means that when the genes responsible for making CoA are "turned on," the cells will also make luciferase and glow. Measuring this light shows how active the CoA genes are. This system helps researchers understand CoA production and screen for compounds that could correct metabolic problems in PANK2-deficient human cells as well as animal models of the disease.

A large-scale screening of 64,168 compounds from a chemical library at Yale University identified 623 active compounds with potential as PKAN therapeutics. Further validation of these hits will be conducted through additional rounds of screening. These compounds will need to be further characterized to determine whether they act as reversal agents and restore normal metabolic function in PANK2-deficient human cells and in living animals with PKAN-like symptoms. The lab will also need to conduct safety and pharmacological studies in mice and initiate in vivo efficacy studies using PKAN mouse models.

While tangible progress has been made in identifying potential candidates, there is still work to be done in identifying a limited number of molecules to be tested. To do this additional screening, new funding is required.

To keep this important work moving forward, Ben Mamoun is applying for a National Institutes of Health (NIH) grant and seeking other sources of funding. We are hopeful that this exciting research will one day lead to a treatment that improves the lives of individuals living with PKAN.

Team NBIA Disorders Raises $120,000 for Gene Therapy Efforts

The NBIA Disorders Association and its dedicated families once again made a powerful impact in this year’s Million Dollar Bike Ride (MDBR), held June 14 in Philadelphia and at local events across North America. With incredible community support, Team NBIA Disorders surpassed fundraising goals for both BPAN and INAD, raising $120,000 for gene therapy research.

Team NBIA Disorders’ BPAN initiative soared past its $50,000 fundraising target thanks to generous contributions and matching partners. Maddie B’s Army, Isabel’s Chance, and Sherri Hansen and Peter Pawlowski pledged a combined $50,000 match, doubling the impact of every dollar raised. Along with community donations and support from fellow BPAN foundations, the total raised for BPAN gene therapy at the Children’s Hospital of Philadelphia (CHOP) reached nearly $110,000.

 MDBR 2025 1
 MDBR 2025 2
BPAN families in North Carolina and Canada held community events to ride, walk, and fundraise in support of BPAN gene therapy.

Participants from around the world joined the effort in honor of their children with BPAN. In Ottawa, Canada, Pete Roy-Smith rode alongside his family and fellow firefighters in honor of his daughter, Poppy. Meanwhile, the Smith family rallied supporters in Shelby, North Carolina, for a local ride and walk in honor of Georgia Smith. Both families have mobilized their communities for many years for this event.

 

In Philadelphia, a dedicated group of riders hit the streets as part of Team NBIA Disorders to honor Quinn Stronski. Representing her family were her father, Paul Stronski, uncle Andy Horowitz, and cousins Helena Horowitz and Patrick Stronski, all riding to accelerate progress in BPAN gene therapy. Their commitment, like that of many others, was instrumental in making the day a big success.

A special thank you goes to the volunteers who helped make the event possible. Among them were the Florio and Mollins families, who managed the Crefeld Street rest stop, offering hydration, snacks and much-needed encouragement to riders throughout the day.

This year, Team NBIA Disorders expanded to include fundraising efforts for multiple NBIA disorders, including INAD/PLAN. The NBIA Disorders Association pledged to match the first $5,000 raised for INAD gene therapy research, and supporters quickly met and surpassed that goal.

The combined effort raised $10,604 to support the INADcure Foundation’s gene therapy project. Among the dedicated participants was Matthew Ritzman, who rode in California with his daughter, Josie, who has PLAN, demonstrating their family’s commitment to advancing INAD research and raising awareness on the West Coast.

From Philadelphia to Canada, North Carolina and beyond, Team NBIA’s presence at the Million Dollar Bike Ride demonstrated the power of a united rare disease community. Donors included individual families, foundations, fundraising teams and generous supporters such as the Roth Family Foundation, Poppy’s Path and the Tziola family. The NBIA Disorders Association is deeply grateful to all who participated in this year’s MDBR.

Every mile pedaled and every dollar raised fuels hope for better treatments and, one day, cures.

 

 MDBR 2025 3  MDBR 2025 4  MDBR 2025 5

 

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