2023 RESEARCH UPDATES
U OF M BPAN GRANT UPDATE
Dr. Rahman has begun to culture a unique line of human induced pluripotent stem cell (iPSC)-derived neurons that enable us to measure and track autophagy in living cells.
Additionally, we contracted with a biotechnology solutions company, GenScript, to manufacture antibodies against WIPI4. This is the protein that is encoded by the WDR45 gene, which is mutated in BPAN. Prior and ongoing studies by BPAN investigators (among others) have been dramatically impacted by the lack of high-quality antibodies against WIPI4. Our antibody is raised against an accessible but distinct region of the protein, offering sensitivity as well as specificity. We should have test samples from GenScript within weeks to begin evaluating for antibody reactivity.
Upcoming plans include:
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Create truncated WIPI4 variants for testing in human iPSC-derived neurons
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Create WDR45 knockout HaloTag-LC3 iPSCs and/or label LC3 with HaloTag in BPAN iPSCs
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Validate WIPI4 antibody candidates from GenScript
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Create lentiviral vectors and generate virus for expression of doxycycline-induced WIPI4 in vivo
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Dr. Maria Castro Bio: https://medicine.umich.edu/dept/neurosurgery/maria-g-castro-phd
Dr. Sami Barmada Bio: https://medicine.umich.edu/dept/neurology/sami-barmada-md-phd
MEYER LAB
The Meyer lab studies neurological and neurodegenerative disorders with the goal to find novel therapeutic avenues of treatment. In particular, we are studying the impact of different patient mutations on disease progression as well as common mechanism between different neurodevelopmental and neurological disorders. Understanding the cellular disease mechanisms might allow us to identify novel therapeutic targets. For BPAN, we are studying cellular disease mechanisms in different cell types of the nervous system using patient skin biopsy derived reprogrammed fibroblasts. We are testing small molecules and different gene therapy approaches for potential future treatment and are recording the response to treatment on a transcriptome level.
Kathrin Meyer, PhD
Assistant Professor & Principal Investigator
Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital
THE PILAZ LAB
The Pilaz Lab is leveraging a novel BPAN mouse model bearing a mutation found in a BPAN patient to answer the following questions:
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Which brain cells and which brain regions are primarily affected in BPAN?
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What is the link between (1) early neurodevelopmental defects and (2) neurodegeneration later in life?
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What is WDR45’s role in brain cells and what are the cellular and molecular defects caused by loss of WDR45 in the brain?
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What therapeutic strategies could help alleviate BPAN symptoms?
Louis-Jan Pilaz, PhD
Sanford Research
Children's Hospital of Philadelphia
We are studying how BPAN affects a child's day to day activities. This will help us to match future clinical trial goals to the needs of the child. Families are joining our research both in person and by tele-research. This allows families from around the world to contribute to our understanding of BPAN. We are using this natural history study to understand overall the different ways BPAN affects children and how this changes over time.
Laura Adang MD PhD
Division of Child Neurology
Children's Hospital of Philadelphia
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GRISHCHUK LAB
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The Grishchuk Lab at the Center for Genomic Medicine is focused on characterizing a preclinical mouse model of BPAN and conducting a proof-of-concept study of AAV-mediated WDR45 gene transfer to rescue neurologic symptoms in BPAN model mice. The timeline of this very important work has been accelerated by 12+ months. If successful this work with provide a proof of concept and can provide a novel therapeutic target for this devastating disease.
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CLINIC FOR BPAN &
WDR45 -RELATED DISORDERS
CENTER FOR GENOMIC MEDICINE, DEPARTMENT OF NEUROLOGY AND CENTER FOR RARE NEUROLOGY DISEASE AT MASS GENERAL HOSPITAL MEDICAL SCHOOL
January 31, 2022
Co – Funded with
Our research is focused on therapy-oriented studies of ultra-rare pediatric neurologic diseases with high unmet medical need. We are supported by Don’t Forget Morgan to perform design and early preclinical development of AAV-mediated gene therapy for BPAN. Having a strong background in studies of autophagy and lysosomal biology in the context of brain health and neurodegeneration, we will also investigate whether either pharmacological or AAV-mediated approaches for autophagy/lysosomal enhancement can compensate autophagy deficits in BPAN, therefore providing novel therapeutic targets for this devastating disease.
RESEARCH
UNIVERSITY OF MICHIGAN
Two Year Grant Awarded to U of M
The University of Michigan's Department of Neurology is home to Sami Barmuda, M.D., Ph.D., and Jason Chua, M.D., Ph.D., two researchers who perform cutting-edge research on the kind of autophagic processes found in BPAN and other NBIA disorders. Dr. Barmuda is the Angela Dobson and Lyndon Welch Research Professor of Neurology at U-M. The laboratory he established in 2013 applies the newest technologies to the study of neurodegenerative diseases. His lab has significant expertise in the study of autophagy, among other areas, and Dr. Chua had the good fortune to spend his residency working under the mentorship of Dr. Barmuda. Dr. Chua is a clinical lecturer in the Department of Neurology, as well as a research fellow and movement disorders clinical fellow. Together, they are investigating the mechanisms which regulate autophagy. Given the young lives they’re racing to save, their research has never been more important.
RESEARCH- SANFORD
Louis-Jan (LJ) Pilaz, PhD
Dr. LJ Pilaz studies the cellular and molecular mechanisms that regulate the development of the cerebral cortex and how their disruption can lead to neurodevelopmental diseases. He received his PhD in Lyon (France), and then moved to the US where he trained as a postdoctoral fellow at Johns Hopkins School of Medicine and Duke University. He is a father to four beautiful daughters.
BPAN SPECIFIC RESEARCH:
Sanford Research was awarded a grant to implement a new technology (called iGONAD) that was initially developed as a partnership between a lab in Japan and another one in Omaha, Nebraska.
When you are using traditional methods, making a mouse model harboring a mutation for a specific gene can be very expensive and takes a lot of time. This technology is a game changer and allows you to get around these two issues.
SANFORD RESEARCH GRANT
July 31, 2020
The goals of our current research grant is to generate novel genetically engineered mouse models (GEMMs) of BPAN. Since BPAN results from reduced expression of the WDR45 gene, the first GEMM will use a knockout approach to replicate the loss of function observed in BPAN patients. The second GEMM will produce a WDR45 protein fused to BioID and will thus enable the identification of the proteins operating in the vicinity of WDR45 in vivo. This will allow the identification of key molecular pathways involved in BPAN disease.
This approach will rely on the iGONAD technique, consisting in the combination of CRISPR technology, together with in utero electroporation one day following fertilization.
The COVID pandemic did not deter us from doing experiments related to this project. Of note, the success of the current experiments conducted in the lab have been inspiring, and will enable us to attack BPAN questions with another angle in future research.
EXPLORATION OF WDR45 FUNCTION AND CONTRIBUTION TO BPAN
SANFORD
October 17, 2020
