NBIA NEWS & INFORMATION

Passing the Torch: Wood to step down as our organization's president September 30th

September 2023

By Sarah Doerr

Board of Trustees Chair

Twenty-seven years after she founded the NBIA Disorders Association, leading it with unwavering dedication, compassion and inspiration that seeded nine sister organizations around the world, our president, Patricia Wood, is stepping down September 30th.

Wood will stay on for two years in a part-time role to mentor her successor, BPAN parent and board member, Amber Denton of Houston. She will also direct our organization’s research program. Her leadership nurtured a strong and stable organization marked by a long list of accomplishments. They include:

• Establishing the biennial NBIA Disorders Association’s International Family Conference. Since Wood organized the first gathering in 2000, our community has come together every other year to reconnect, learn from one another and the experts, and celebrate the lives of our loved ones affected by NBIA disorders

• Expanding an international community of NBIA researchers, including committee planning for eight scientific symposia that continue cultivating the world’s best minds to study NBIA. The symposia bring together experienced and early-career researchers to share and build upon one another’s work

• Continuous fundraising to support NBIA research, resulting in the publication of scientific articles and the discovery of genes associated with certain NBIA disorders

• Leading a memorable $250,000 campaign in 2009 to keep the lab of our premier researcher, Dr. Susan Hayflick, afloat when federal funding dried up

• Being a world leader in NBIA and helping to create the NBIA Alliance. The alliance is the umbrella organization with our organization as fiscal sponsor of NBIA patient organizations in 10 countries that collaborate to support NBIA-affected families and educate the public, along with funding and promoting the advancement of potential treatments

• Serving as a critical partner in the $7.8 million international grant known as TIRCON, for Treat Iron-Related Childhood-Onset Neurodegeneration. The TIRCON International Patient Registry was created, and the grant supported a PKAN clinical trial for deferiprone 

As impressive as each of these achievements is, the community Wood has built among NBIA families is her most significant contribution. When a family receives an NBIA diagnosis for a loved one and finds the NBIA Disorders Association, Wood is their first point of contact in our growing community. She offers support, information, connections and most importantly, hope, to hundreds of families. Wood says that a key reason she founded the NBIA Disorders Association was because of the loneliness and despair her family experienced when her daughter, Kimberly, was diagnosed with NBIA. She didn’t want other families to walk that rocky path alone.

“One of my goals from the start was to build a strong community so that we can emotionally support and learn from each other and find happiness and friendship as part of our journey in searching for treatments and cures for all our NBIA individuals,” she says.

Patricia Wood announcing at the conference that she is stepping down as president on September 30. She welcomed Amber Denton to the stage as the next president, who then shared her vision for the future. You can listen to both speeches here.

Wood announced in Houston at the biennial family conference in May that she would be stepping down. She received a standing ovation after speaking about the gratitude and honor she has felt while helping to shape the organization’s past, present and future. She has worked closely with her successor for the past four years and says she enthusiastically supports the board of trustees’ choice of Denton.

Denton has been a board member since 2019 and currently serves as vice president. She also chairs the organization’s Development Committee, the lead role in fundraising. She has been an active member of our community since her daughter Sydney’s BPAN diagnosis in 2017. Board members are confident in Denton’s leadership skills, empathy, and drive to lead our organization into its next chapter.

“It is with immense pride and dedication that I assume the role of president,” Denton says. “I am deeply honored to follow in the footsteps of Patricia Wood and continue the impactful work that she has done for our community.

With a profound commitment to advancing research, providing support to our families and raising awareness, I am eager to collaborate with all of you to drive positive change for those affected by NBIA disorders. My vision is to build upon the foundation of the past 27 years, ensuring that every individual and family touched by NBIA disorders finds solace, resources and hope within our community.”

For those of us who weren’t at that first family conference in 2000, it’s hard to imagine a time when there wasn’t an NBIA Disorders Association to provide community and connection in our corner of the rare disease world. We are thrilled to have Denton continue in the spirit of our outgoing leader. I speak for the board when I say, “Patty, your vision and passion will continue to inspire us for many years to come.”

NBIA Disorders Association awards first NBIA Center of Excellence in U.S.

September 2023

By James A. Bourgeois

The NBIA Disorders Association has awarded the Oregon Health & Science University in Portland its first Center of Excellence designation for exceptional work in NBIA care and research.

The NBIAcure team at Oregon Health & Science University are recognized for their exceptional work and receive the first Center of Excellence designation from NBIA Disorders Association at family conference in May.

The designation, made possible by the efforts of the NBIAcure team led by Dr. Susan Hayflick at OHSU, was announced at our organization’s international family conference in May. It recognizes the high-level of expertise that OHSU and NBIAcure bring to NBIA research and clinical care. Hayflick, Dr. Penny Hogarth and other members of the team are international NBIA leaders and have distinguished themselves in the field for decades.

“It’s a real honor to be recognized in this way,” Hayflick said, coming to the conference podium to receive a plaque with the designation.

Dr. Susan Hayflick accepts Center of Excellence plaque from Dr. James Bourgeois, who serves on the board of trustees and is chair of the association’s Clinical and Research Development Committee.

The award is the culmination of a nearly yearlong effort by our Clinical and Research Development Committee, created last summer, to designate NBIA Disorders Association Centers of Excellence (COE) and Clinical Care Centers (CCC) in the United States. These designations help NBIA families find excellent and experienced NBIA care closer to home, with COEs being our highest classification level because of their clinical research activities.

Members of the committee use their professional and institutional connections to encourage further development of clinical care and research into NBIA disorders. The committee also partners with medical centers that seek to attain this recognition. The committee envisions a network of COE and CCCs to serve NBIA patients and their families, as well as collaborate with our organization on clinical care and clinical research.

Along with me, members of the committee are Kathleen Ayers of Sacramento, California; Steve Pirnie of Providence, Rhode Island; Loreen Pirnie also, of Providence; Eric Pozsgai of Columbus, Ohio; Maryann Ruchirushkul of Houston, Texas; Reed Mollins of High Falls, New York; and Cheryl Lamos of Albany, New York.

We welcome additional committee members who are in the health professions, the research community, and/or health care administration. Anyone who is interested in learning more can contact me at jbourgeois@ucdavis.edu.

James Bourgeois of Sacramento, California, serves on the NBIA Disorders Association Board of Trustees and works at the University of California, Davis, as Clinical Professor of Psychiatry. He is chair of the association’s Clinical and Research Development Committee.

BPAN researcher develops stem cell model, awaits funding for planned drug screening

September 2023

By Patricia Wood 

Dr. Paul Lockhart of Murdoch Children's Research Institute of Melbourne, Austrailia, establishes "brain cell" model for BPAN research.

Dr. Paul Lockhart of Murdoch Children’s Research Institute in Melbourne, Australia, says that while his BPAN research established an important ‘brain cell’ model using stem cells from affected BPAN individuals, his next step — to screen drugs for treatment — awaits sufficient funding to proceed.

Lockhart received $60,561 in February 2020 from the 2019 Million Dollar Bike Ride grant
program that our families supported. He planned to do the drug screening after his initial findings, but the pandemic led to staffing shortages and much higher drug screening costs than anticipated. As a result, he returned $25,814 in unspent funds this spring. That money was added to this year’s funds raised for the University of Pennsylvania sponsored bike ride and will now help fund two $60,000 BPAN research grants in the current grant call underway. 

Lockhart says the model he developed with stem cells from BPAN individuals will be used to
screen 3,000 compounds approved by the Food and Drug Administration in the search for a
BPAN treatment. The screening process will require multi-year funding to identify drugs capable
of restoring the normal cell functioning called autophagy, which is the removal and recycling of
damaged cells.

Lockhart’s project was titled “Development of novel human stem cell models of BPAN for disease modeling and drug screening” and was part of a larger project that was the first research into BPAN undertaken in Australia. It was made possible in 2019 with an anonymous $200,000 donation in honor of Angus Hunter, who has BPAN. The Hunters live in Melbourne and are active in raising awareness and funds for BPAN research.

Lockhart’s team used skin cells from six affected children. These samples were converted into induced pluripotent stem cells (iPSCs), which can then be converted into almost any type of human cell.

The team also did gene editing to generate an identical matching (isogenic) iPSC that corrected the genetic change causing BPAN. The researchers converted these matched pairs into brain cells in a lab dish and analyzed them to determine what effect the genetic change was having on cell structure and function. These biochemical studies investigated how well the autophagy pathway operated in the mutant cells.

A talk on this work given at our 2021 family conference BPAN research update session can be viewed here starting at the 3:25 minute mark.

Lockhart, who spoke at our 2021 family conference about this work, said that
a method from the iPSC was developed for successfully generating neurons
and also glia that essentially work normally. This demonstrated that there was
no significant impact of the genetic change on the ability of cells to survive,
convert to different types of brain cells and form the linkages between cells
that are critical for brain function.

Furthermore, analysis of the autophagy pathway demonstrated that this was
not functioning properly in affected cells compared to the controls. This finding
confirmed that the iPSC model could replicate what has been observed in other
cell and animal models, demonstrating its utility as a preclinical model to
understand the effect of BPAN on brain function. Although Lockhart was not
able to complete additional studies, his group demonstrated that rapamycin, an
FDA approved drug, could increase autophagy activity in the model.

This ‘brain cell’ preclinical model of BPAN is important, Lockhart said, because
it “means we can generate the brain cell types that are specifically affected in 
individuals with BPAN. This includes cortical neurons, important for cognitive function, and dopaminergic neurons, which are important for movement.”

Lockhart plans to publish his results and will undertake drug screening when funding allows.

2022 Million Dollar Bike Ride results in $69,775 for BPAN research

April 2023

Professor Betrand Mollereau of ENS-Lyon in France, was the 2022 MDBR research grant recipient.

Thanks to fundraising efforts by BPAN families and a matching grant from the University of Pennsylvania’s Orphan Disease Center, new BPAN research is now underway to better understand what causes the disease.

Professor Bertrand Mollereau of Ecole Normale Supérieure de Lyon, (ENS-Lyon) in France, received $69,775 as the 2022 BPAN research grant recipient from this annual in-person and virtual bike-riding event.

Mollereau and his co-investigators on the project at ENS-Lyon, Dr. Ludivine Walker and Marion Celle, will spend a year studying autophagy. Autophagy is the cell’s housekeeping and recycling process in which a cell breaks down old, damaged or abnormal parts and reuses some of them to keep the body functioning smoothly. Sometimes, however, the process doesn’t work the way it should.

Defective autophagy has been observed in several BPAN cellular and animal models. Some scientists think insufficient autophagy could be responsible for neurodegeneration in BPAN patients. Hence, a research priority is identifying novel therapeutics that restore the cleaning-and-recycling system.

Collaborating with Mollereau’s lab on the project is Dr. Apostolos Papandreou of University College London. He and colleagues at the Kurian/Ketteler laboratories at UCL have identified small molecule compounds that correct autophagy in certain types of stem cells taken from BPAN patients known as cultured induced pluripotent stem cells (IPSC).

An important step in selecting the best compounds is to show how well they work in an animal model of the disease. For this purpose, Mollereau and co-investigators have developed an animal fly model of BPAN that exhibits hallmarks of the disease, such as an autophagy defect, iron accumulation, neurodegeneration and a movement disorder.

For his part of the project, Papandreou will continue characterizing compounds in IPSC. These cells have unique properties of self-renewal and can be made into many other types of cells. Mollereau and co-investigators will select the best molecule compounds that restore autophagy to these stem cells to see if they can rescue the cellular and movement defects in BPAN flies.

The resulting compounds will then be tested in a larger animal, with a goal of creating a clinical trial to see if one or more of these compounds might benefit BPAN individuals.

Mollereau’s project is titled “Establishing autophagy inducers as novel therapies in cellular and animal models of Beta-propeller Protein-Associated Neurodegeneration (BPAN).”

Two MPAN grants worth $140,000 awarded to further disease insights

 December 2022

The NBIA Disorders Association, along with three sister organizations in Europe, have awarded two MPAN grants that will forward research priorities set during a workshop on Mitochondrial Membrane Protein-Associated Neurodegeneration.

Dr. Lena F. Burbulla of the Ludwig-Maximilian University in Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, each received one-year research grants of $70,000 to study MPAN.

The funding was made possible through an international collaboration that also included the Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF) in Italy, Hoffnungsbaum e.V. in Germany and Stichting Ijzersterk in The Netherlands.

In a 2021 workshop led by Dr. Francesca Sofia, founder and chief executive of Science Compass in Milan, Italy, researchers collaborated to collect data as well as assess strengths, challenges, and trends in MPAN research to establish a set of scientific priorities. For details, see page 8 of our December 2021 Newsletter.

Dr. Lena Burbulla of Ludwig-Maximilian University in Munich, Germany, receives a $70,000 research grant to study MPAN in December.

Burbulla’s research involves human disease modelling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so her lab uses induced pluripotent stem cells (iPSCs) generated from skin cells from people affected with MPAN. Burbulla’s team will utilize these stem cells – that theoretically can be turned into any type of cell in the body – to generate dopaminergic nerve cells that are known to be affected in MPAN patient brains. Dopaminergic nerve cells produce the neurotransmitter dopamine, a chemical messenger involved in regulating body movements, memory, motivation, attention, learning and more.

Mutations in one specific gene, C19orf12, are the only known cause of MPAN. The function of the resulting protein C19orf12 remains largely unknown. Disease modelling approaches will help the researchers examine, in a patient-specific model, the C19orf12 protein function and, most importantly, how brain cells are impacted when this protein is impaired or lost. Burbulla and her team will investigate the effect of loss of C19orf12 function in mitochondrial health in these patient nerve cells. The mitochondria are the “powerhouses of the cell” producing about 90% of the energy cells need to survive. When mitochondria are damaged, disastrous consequences for the cell can occur, along with a toxic series of events that culminate in nerve cell death. Given that the C19orf12 protein is known to associate with mitochondria, its loss of function may affect mitochondria and have wide-ranging impacts on cell health and resilience.

The stem cell model will enable the researchers to compare the MPAN cells to healthy cells and better understand the protein’s role. They will also look beyond mitochondria for disease-associated pathology, probing for possible alterations in the processing of the neurotransmitter dopamine in these nerve cells, as well as a protein called alpha-synuclein, known to pathologically accumulate in MPAN patient brains.

Alpha-synuclein is found on the ends of nerve cells in the synaptic terminals — the area between neurons where the neurotransmitters are released to relay messages throughout the body. Abnormally shaped or overly abundant alpha-synuclein leads to aggregation, or clustering, of the proteins and inhibits normal neuron function.

Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, in Rochester, New Jersey, receives a $70,000 grant to research MPAN in December.

Baharadwaj’s research will focus on better understanding the proteins produced by the C19orf12 gene. His team will use fruit fly models that have been genetically engineered to lack the CG3740 and CG11671 genes, which correspond to the C19orf12 gene in humans.

Previous studies from other groups and his ongoing work have shown that the model flies have shorter life spans, deficits in movement and loss of neurons in the brain and retina. This suggests that the fruit flies will be a promising model to study NBIA.

The team’s studies also suggest the C19orf12 is a membrane contact site protein that may be involved in communication between organelles, specialized subunits within the cell, such as the endoplasmic reticulum and lipid droplets (fats). The endoplasmic reticulum’s role in the cell is to produce proteins, and it’s involved in the production and storage of lipids.

The team’s goal is to study how the C19orf12 protein is involved in lipid metabolism and mitochondrial function. Lipid metabolism is the process of production and degradation of lipids, or fats, in cells. The researchers want to uncover this role in the brain and other organs. Both lipid metabolism and mitochondrial function are implicated in other forms of NBIA as well.

Overall, the creation and study of these disease models and subsequent research will advance the understanding of MPAN and pave the way for developing treatments.