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他和他的实验室的创新方法为推进β -螺旋桨相关神经退行性变(BPAN)和其他疾病的治疗提供了新的机会。
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.
Meyerink说:“这为未来的治疗探索奠定了基础，并为疾病研究提供了一个平台，以生成具有患者特异性突变的模型。”
他很高兴能将这项技术应用于其他疾病，尤其是其他罕见的儿科疾病，并认为这是一个机会，使他在继续他的教育和培训中熟练使用这种方法。
BPAN仍然是一种毁灭性的疾病，导致儿童患者的早期死亡。由于缺乏动物模型和对这种疾病如何影响大脑导致患者早死的知识，人们对这种疾病的了解还不充分。
考虑到这项工作对治疗发现的价值，Pilaz博士说:“虽然以前的小鼠系可能有助于研究大脑中WDR45蛋白的功能，但一个更强大的带有患者突变的小鼠模型将有助于发现和验证有效治疗患者的方法。”
“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
- Rare, but not alone: CoRDS connects rare disease patients
- Sanford Research president leads global rare disease group
- Brain researcher L-J Pilaz is ‘like a discovery junkie’
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Posted InBrain & Spine,Children's,Genetics,Research
