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

from | December 17, 2023

Dr. Paul Lockhart of the Murdoch Children's Research Institute in Melbourne, Australia, says that while his BPAN research has developed an important "brain cell" model using stem cells from affected BPAN individuals, his next step - screening (systematic series testing) of drugs for treatment - is still awaiting adequate funding.

Dr. Paul Lockhart

Lockhart received $60,561 in February 2020 from the 2019 Million Dollar Bike Ride (MDBR) grant program, which US families have supported. He planned to conduct drug screening after his initial findings, but the pandemic led to staff 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 donations to the University of Pennsylvania-sponsored MDBR and will now help fund two $60,000 BPAN research grants under the current solicitation.

Lockhart says the model he developed using stem cells from BPAN patients will be used to screen 3,000 Food and Drug Administration (FDA)-approved compounds in search of a BPAN treatment. The screening process will require several years of funding to identify drugs that can restore normal cell function, known as autophagy, which is the degradation and recycling in 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 on BPAN in Australia. It was made possible by a $200,000 anonymous donation in 2019 in honor of Angus Hunter, who suffers from BPAN. The Hunters live in Melbourne and are actively involved 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 (iPSC), which can then be transformed into almost any type of human cell.

The team altered the gene to create an identical, matching (isogenic) iPSC that corrects the genetic change that causes BPAN. The researchers transformed these identical pairs into brain cells in a lab dish and analyzed them to determine what effects the genetic change had on cell structure and function. These biochemical studies examined how well the autophagy process worked in the mutant cells.

Lockhart, who spoke about this work at the 2021 NBIA Disorders Association Family Conference, said that a method was developed from the iPSCs to successfully generate neurons and also glial cells that essentially function normally. This showed that the genetic modification had no significant effect on the cells' ability to survive, to transform into different types of brain cells and to form the connections between cells that are critical for brain function.

In addition, analysis of autophagy metabolism showed that it was not functioning properly in the affected cells compared to control subjects. This finding confirmed that the iPSC model can reproduce what has been observed in other cell and animal models and demonstrates its usefulness as a preclinical model for understanding the effects of BPAN on brain function. Although Lockhart was unable to conduct further studies, his group was able to demonstrate that rapamycin, an FDA-approved drug, can increase autophagy activity in the model.
This preclinical "brain cell" model of BPAN is important, Lockhart says, because it "means that we can generate the brain cell types that are specifically affected in individuals with BPAN. These include cortical neurons, which are important for cognitive function, and dopaminergic neurons, which are important for movement."

Lockhart plans to publish his findings and will conduct a drug screening as soon as funding is secured.

Translation of the original article by Patricia Wood from the September NBIA DA newsletter:

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