NBIA NEWS & INFORMATION

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).”