Research into rare brain disease gets a boost

Don’t Forget Morgan Foundation supports Sanford Research scientist’s work

Little girl with BPAN, a rare brain disease, plays in front of a fireplace in her living room.

Research at Sanford Health has the potential to save the lives of children with a rare genetic brain disorder that’s been compared to Parkinson’s disease.

L-J Pilaz, Ph.D., and his lab’s innovative approaches provide new opportunities for advancing treatment of beta-propeller associated neurodegeneration, or BPAN, and other diseases.

BPAN is a rare disease characterized by progressive damage to the nervous system resulting from mutations in the gene WDR45. Children with BPAN experience intellectual disability, seizures, difficulty coordinating movements such as walking, and developmental delays. As the disease worsens, patients display cognitive decline and dementia, experience greater difficulty walking, and can develop tremors which impair motor skills.

Only an estimated 500 to 2,000 people in the world have BPAN. Due to the rare nature of this disease, treatments are focused on managing a patient’s symptoms and not the disease itself.

BPAN work at Sanford Research

The work of Dr. Pilaz and his team aims to better understand how BPAN disease impacts the brain so that targeted therapies for patients can be explored in the future. In fact, Dr. Pilaz recently received a grant from the Don’t Forget Morgan Foundation.

The foundation is a nonprofit organization started by the parents of Morgan Kozole, a 6-year-old in Michigan who has the rare neurological disease. Dr. Jill Weimer, a developmental neuroscientist at Sanford Research, served on the foundation’s scientific advisory board.

To study disease, scientists often need to use animal models to better understand the impact of the disease and discover viable treatments to help patients. These treatments usually target particular pathways in the body — a domino effect required for healthy function — that are affected by disease. Currently, animal models of BPAN disease do not show the same disease symptoms that are observed in humans, including early death.

“While BPAN is caused by mutations of the WDR45 gene, we do not have a clear knowledge of the pathways regulated by WDR45, especially in the developing brain,” Dr. Pilaz said.

Using an emerging technology, Dr. Pilaz’s group is working to “generate genetically engineered mouse models, in which WDR45 bears a mutation comparable to those observed in human patients.” Their preliminary findings indicate that this mutation genetically models the human disease and shows promise in repeating the developmental delay.

“Based on the current data, it is tempting to speculate that our new model will be effectively mimicking the impact of WDR45 loss in humans,” Dr. Pilaz said. “The proposed project will characterize this novel BPAN mouse model together with another uncharacterized one generated by UC Davis to provide insights into the role of WDR45 during brain development, thus enabling us to better understand how WDR45 loss leads to BPAN disease.

“This work showcases the lab’s ability to generate tailored mouse models for human disease.”

Foundation for future brain disease therapy

The use of these cutting-edge techniques also provides opportunities for trainees like Brandon Meyerink, a third-year Ph.D. student in the lab. Meyerink’s work includes generating these genetically engineered mouse models.

“It lays a foundation for future therapeutic exploration and provides a platform to generate models with patient-specific mutations for disease study,” Meyerink said.

He is excited to apply this technique for work with other diseases, especially other rare pediatric diseases, and sees this as an opportunity to become skilled in this method as he continues his education and training.

BPAN continues to be a devastating disease that leads to early death in childhood patients. The disease is not well understood due to a lack of animal models and knowledge of how the disease affects the brain to contribute to early death in patients.

Thinking ahead to the value of this work for therapeutic discovery, Dr. Pilaz said, “While previous mouse lines may be useful to study WDR45 protein function in the brain, a more robust mouse model with a patient mutation will be beneficial to discover and validate approaches to treat disease patients effectively.

“The Don’t Forget Morgan Foundation, who funded this project, was created by the parents of kids suffering from BPAN and who are currently 3 to 7 years old. It is a race against the clock to get those therapies to work.”

Learn more

Posted In Brain & Spine, Children's, Genetics, Research