BPAN researcher develops stem cell model, awaits funding for planned drug screening
September 2023
By Patricia Wood
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| 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.
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| 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.
