NBIA NEWS & INFORMATION

By: Patricia Wood

July 2024

Photo credit: Jan Greune (LMU)

Professor Lena Burbulla, Ludwig Maximilian University, Munich, Germany

In November 2022, the NBIA Disorders Association, along with three sister organizations in Europe, awarded two Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) grants of $70,000 each. These one-year grants were awarded based on priorities set during an MPAN workshop that was part of an MPAN Landscape Analysis project also funded by these same organizations.

Prof. Lena Burbulla of the Ludwig Maximilian University of Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, recently completed their research under this funding and have both reported promising findings.

The funding was made possible through an international collaboration that included AISNAF in Italy, Hoffnungsbaum e.V. in Germany, and Stichting Ijersterk in The Netherlands.

Burbulla’s research involved human disease modeling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so, her lab used induced pluripotent stem cells (iPSCs) generated from the skin cells of people affected with MPAN.

Brains of MPAN patients show massive loss of nerve cells in specific regions, predominantly a region in the midbrain called the substantia nigra. Here, the loss of cells producing the neurotransmitter dopamine is substantial and anticipated to be responsible for the vast majority of clinical symptoms. Therefore, Burbulla’s team used stem cells from MPAN patients and converted them into midbrain-specific dopaminergic nerve cells — the type of cells that degenerate in the brains of individuals affected by MPAN — to identify mechanisms specifically affecting this vulnerable cell type.

They were able to remarkably recapitulate important aspects of the disease pathology found in patient brains making patient-derived dopaminergic nerve cells a valuable model to study disease-specific phenotypes in a dish.

They also observed an accumulation of alpha-synuclein, a presynaptic protein known to aggregate in the brains of MPAN patients, a signature of iron misregulation leading to iron overload as well as axonal swellings that have been observed in postmortem brain biopsies.

Unbiased proteomic studies revealed some key mitochondrial proteins to be dysregulated and multiple proteins related to neurotoxicity and activation of the brain’s immune response to be enhanced. This unique protein signature may give a first insight into why dopaminergic nerve cells in the brains of patients are specifically vulnerable and degenerate.

Burbulla states that one of the most promising advantages of human iPSCs is their utility as a patient-specific disease model, offering the opportunity to gain deeper insights into disease mechanisms and progression. In this study, they demonstrated that iPSC-derived MPAN patient nerve cells recapitulate aspects of human disease pathology and therefore serve as a valuable model to better understand the disease-specific mechanisms underlying loss of C19orf12 function.

Burbulla plans to publish their results and hopes to conduct further studies using patient-derived disease models to guide future rescue strategies in the hope of identifying new therapeutic approaches to combat MPAN.

Dr. Rajnish Bharadwaj, University of Rochester Medical Center, Rochester, New Jersey

Bharadwaj’s research used fruit fly models that have a gene called nazo whose human counterpart is C19orf12, the gene that causes MPAN in humans. Using these fruit flies, Bharadwaj showed that Nazo protein is required for the maintenance of lipid droplets, which are storage sites for triglycerides (fat). In its absence proteins involved in curbing the utilization of fat (by lipolysis) are diminished. The loss of the nazo gene has a significant impact on the lifespan and health of the fly.

Bharadwaj is working on gaining a deeper understanding of the alterations in lipid droplets in flies lacking the nazo gene. Interestingly, human C19orf12 protein is highly enriched in adipose (fat) tissue. Bharadwaj’s findings suggest that lipid abnormalities may contribute to neurodegeneration in humans.

Bharadwaj has already published a paper on his findings that can be found here in PLOS Genetics: Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis | PLOS Genetics

He plans to use the data accumulated with this grant to get NIH funding to carry the work forward. It is hoped that this study will provide the foundation for future investigations into the role of the human C19orf12 protein in NBIA.

The NBIA Disorders Association, along with its international NBIA Alliance partners, remains committed to advancing research that brings us closer to understanding and ultimately curing MPAN. As we celebrate these advancements of Burbulla and Bharadwaj, we look forward to further breakthroughs that will improve the lives of those affected by NBIA disorders.

NBIAcure Prepares to Submit for FDA Approval of CoA-Z Compound

March 2024

By Amber Denton

Dr. Penelope Hogarth and Dr. Susan Hayflick, NBIAcure Oregon Health & Science University, Portland, Oregon

NBIAcure, a research team led by Dr. Susan Hayflick and Dr. Penny Hogarth and based at Oregon Health & Science University (OHSU), has released a significant update to the Pantothenate Kinase-Associated Neurodegeneration (PKAN) community regarding the status of CoA-Z, a vitamin intermediate. In January, the team announced their decision to approach the U.S. Food and Drug Administration (FDA) based on the strength of gathered data rather than pursue additional studies.

The FDA will evaluate data from the clinical trial to assess the safety and tolerability of CoA-Z and its effect in altering a biological marker of PKAN in the blood. Trial results indicate that CoA-Z altered the blood biomarker in a dose-dependent manner, with higher doses yielding a greater response.

A critical outcome of the trial is demonstrating CoA-Z's safety. This involves establishing that possible side effects occur with the same frequency, whether a participant was on a placebo or one of three doses.

The initial six months of the trial were conducted in a double-blind, placebo-controlled manner to meet the most rigorous scientific requirements. This approach demonstrates to the FDA that the research was done with the greatest integrity to protect against potential bias. Analysis of this phase confirmed CoA-Z's safety and tolerability across all tested doses.

The team is finalizing the report for this phase alongside other essential information, including the manufacturing process, stability under varied conditions, and effects on animal models. The target is to submit a draft application to the FDA by the end of March, a goal that remains on track.

Although the exact timeline for the FDA's review of the draft remains uncertain, the agency has suggested that conducting a preliminary assessment before final submission could minimize future delays. The team will advocate for expedited review while valuing the time and attention given to the review process. Meanwhile, the focus will shift to analyzing data from the trial's open-label portion, where all participants received the same dose of CoA-Z for inclusion in the final submission.

In February, Dr. Penelope Hogarth, part of the NBIAcure team at OHSU, presented the clinical trial results at the 8th International Symposium on Pediatric Movement Disorders in Barcelona, Spain. Numerous PKAN specialists attended the symposium and expressed excitement about the findings.

NBIAcure and the Spoonbill Foundation partners remain hopeful that the presented data will suffice to convince the FDA that additional studies are unnecessary. The team extends their gratitude to the PKAN community for their support and encouragement throughout this process.

2023 Million Dollar Bike Ride Results in $120,000 for BPAN Research

March 2024

By Patricia Wood

The 10th annual Million Dollar Bike Ride (MDBR), hosted by the University of Pennsylvania’s Orphan Disease Center, resulted in two NBIA researchers each receiving a $60,000 grant to study Beta-Propeller Protein-Associated Neurodegeneration (BPAN).

NBIA Disorders Association has participated in this annual event, raising funds for research since 2018. In all, ten BPAN research grants have been awarded, totaling $590,714.

Our organization prepares the request for proposals and selects the grant reviewers. The University of Pennsylvania manages the grants and sends us copies of the scientific reports that grant recipients provide. They also provide $30,000 in matching funds for the first $30,000 raised. The current funding period runs from February 1, 2024 – January 31, 2025.

Our two grant recipients are Dr. Mario Mauthe from the University Medical Center Groningen, the Netherlands, and Dr. Manju Kurian from University College London, United Kingdom.

Dr. Mario Mauthe, University Medical Center Groningen, The Netherlands

When mutated, the WDR45 gene codes for a protein called WDR45, which leads to BPAN. This protein is involved in autophagy, a process responsible for degrading and recycling damaged cellular components. The mutated WDR45 protein also affects cellular organelles called mitochondria, which play vital roles in energy production, metabolism regulation and immunity. Mitochondrial dysfunction is not unique to BPAN and is also observed in several other NBIA disorders, such as PKAN, CoPAN, PLAN and MPAN.

This project will investigate how mutations in WDR45 affect and interfere with mitochondria structure and function and how these alterations contribute to the BPAN pathophysiology. In particular, they will look at WDR45’s role in maintaining mitochondrial homeostasis and they will also identify potential drugs reversing mitochondrial dysfunction caused by WDR45 mutations.

To understand the role of WDR45 in mitochondrial dysfunction, Mauthe’s team will focus on studying the proteins involved in mitochondrial functions that are misregulated in WDR45 defective cells. For their investigations, they will use various cutting-edge research methods such as proteomic analyses, generation of induced neurons from patient fibroblasts, automated live cell imaging, and ultrastructural examination of mitochondria.

In addition, they aim to identify pharmaceutical compounds that can rescue mitochondrial dysfunctions observed in WDR45 defective cells. They will utilize an automated imaging system to evaluate drug effects on these cellular phenotypes.

Dr. Manju Kurian, University College London, United Kingdom

Our other grant recipient, Kurian, is focusing on gene therapy for BPAN. Her group has experience working on gene therapy for PLA2G6-Associated Neurodegeneration (PLAN), another NBIA disorder, which Bloomsbury Genetic Therapies Limited is now moving forward.

The project proposes to develop gene therapy to deliver a healthy copy of the faulty BPAN gene directly into the brain. The aim is to establish a state-of-the-art laboratory model of disease (a ‘brain in a dish’) and use an excellent mouse model that shows key features of human disease to evaluate this gene therapy approach and see whether it rescues the problems caused by the faulty gene in BPAN.

A successful gene therapy study in their laboratory will allow them to accelerate a clinical gene therapy trial for children with BPAN. They hope gene therapy will halt disease progression, increase life expectancy, and provide a better quality of life for individuals and their families living with this condition.

We are grateful for the long-time support of Mauthe and Kurian and their dedication to NBIA research. These grants would not have been possible without the commitment of our community members who participate in fundraising for the Million Dollar Bike Ride each year. We also thank the Orphan Disease Center for their generous $30,000 match and their eagerness to fuel research for rare diseases.