NBIA NEWS & INFORMATION

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.

Advancing PKAN Gene Therapy: A Collaborative Effort

March 2024

By Amber Denton

Pantothenate Kinase - Associated Neurodegeneration (PKAN) gene therapy continues to move forward due to dedication from veteran researchers and newly found partnerships.

In 2019, a significant stride in PKAN research was made when the NBIA Disorders Association, in collaboration with sister NBIA organizations AISNAF (Italy) and Hoffnungsbaum e.V. (Germany), provided initial funding to Dr. Lauriel Earley at the University of North Carolina – Chapel Hill to initiate gene therapy research. However, scientific endeavors are often subject to unexpected shifts.

Earley's decision to discontinue her PKAN work necessitated a seamless transition to Dr. Susan Hayflick at Oregon Health & Science University (OHSU). In 2019, Hayflick committed to taking the reins, bringing with her a wealth of experience and a deep commitment to advancing PKAN research. Dr. Suh Young Jeong, Hayflick’s scientific team leader since 2014, was able to carry the project to completion with very promising results.

The project's changing of hands has continued to breathe life into PKAN gene therapy.

Recently, Hayflick was contacted by the Loving Loic Foundation, a nonprofit started by Sherine and Mark Blackford in honor of their son, Loic, who has PKAN. The Blackfords were personally interested in the advancement of gene therapy and offered their support.

The Loving Loic Foundation facilitated an introduction to Dr. Miguel Sena-Esteves and Dr. Heather Gray-Edwards at the Horae Gene Therapy Center at UMass Chan Medical School (UMass.) Sena-Esteves, an expert in developing adeno-associated virus (AAV)-based gene therapies, and Gray-Edwards, an expert in utilizing animal models to enhance understanding of disease progression, agreed to partner with Hayflick’s team. Additionally, Dr. Penelope Hogarth from OHSU joined the team, bringing years of PKAN experience and expertise in clinical trial design. The clinical trial team also includes Allison Gregory, genetic counselor, Dr. Jenny Wilson, child neurologist, and Alison Freed, clinical research coordinator.

Recent progress reports show that the team is redesigning the gene therapy drug to optimize its therapeutic effects. Using the PKAN mouse colony that the OHSU team developed over the past two decades, they will test several redesigned products to determine which performs best. This elaborate process is expected to require at least two years to complete, depending on U.S. Food and Drug Administration (FDA) input. While these critical experiments are underway, they will also be hard at work designing and preparing for the clinical trial. It is imperative that regular meetings with the FDA are held at every step of the process. FDA feedback and suggestions may impact the timeline of progress. Currently, the team is unsure when a clinical trial for PKAN gene therapy will begin, but they also feel the urgency like those in the PKAN family community do.

As the researchers are making great strides in the laboratory, the Loving Loic Foundation continues to play a pivotal role in supporting this collaborative endeavor, providing crucial financial backing and advocacy efforts, recently receiving a $21,000 grant to bring the total amount raised to $182,036 (including in-kind donations) towards the $5 million project goal. If you are interested in learning more, fundraising or contributing to this cause, please visit lovingloic.org or contact Sherine Blackford at info@lovingloic.org.

$60,000 Grant Awarded to study decreased Mitochondrial Energy Production in BPAN

December 2023

Dr. Arcangela Iuso from the Helmholtz Zentrum München’s Institute of Neurogenomics in Munich, Germany, has been awarded a one-year grant of $60,000 from our organization. Her project was selected from seven applications submitted for our BPAN grant call this past spring.

Arcangela Iuso, from the Helmholtz Zentrum München’s Institute of Neurogenomics in Munich, Germany.

Iuso’s project focuses on understanding why mutations in the WDR45 gene lead to reduced energy production by mitochondria, considered the powerhouses of the cells. This defect was initially pinpointed in the brain tissue of a BPAN mouse model. It appeared to be linked to the malfunctioning of a specific mitochondrial enzyme known as Respiratory Chain Complex I (RCCI), a discovery that Iuso co-authored in a 2021 publication available here.

Recently, the defect of RCCI was also identified in muscle and skin cells of a BPAN patient with the findings presented by Dr. Anna Ardissonne at the 8th International NBIA Symposium held last October in Lausanne, Switzerland.

Iuso's current project aims to clarify if the enzymatic issue affects all brain cells uniformly or if specific cell populations, such as neurons or their supporting cells, are more susceptible. To investigate this, Iuso's laboratory will generate neurons and supportive cells using induced pluripotent stem cells (iPSCs) derived from the skin cells of individuals affected by BPAN. This methodology will help pinpoint the precise brain cell type the enzymatic deficiency impacts.

The subsequent phase involves exploring therapeutic compounds that could potentially restore the enzymatic activity of RCCI within the laboratory setting. Iuso aims to evaluate natural compounds or FDA-approved molecules in the hopes of identifying a potential therapeutic approach for BPAN.

Poland's NBIA Meetings Unite Global Community

December 2023

In October, the international NBIA community witnessed a series of significant moments. These gatherings represented an important stride in advancing research and collaboration within our community.

Researchers, clinicians, and patient advocacy leaders at the BPAN Workshop in Warsaw, Poland, October 17-18.

As the Research Program Director for our organization, I had the privilege of participating in impactful gatherings - a BPAN Workshop, NBIA Poland’s first conference and an NBIA Alliance meeting. Being part of these sessions proved very rewarding as I witnessed the passion and commitment among our dedicated researchers, clinicians, and patient organization leaders.

The BPAN Workshop's goal was to identify and address opportunities for therapeutic development in Beta propeller Protein-Associated Neurodegeneration (BPAN). It was organized by our sister organization, Stichting Ijzersterk, in collaboration with three European BPAN researchers: Rachel Wise of Ludwig Maximillian University in Germany, Mario Mauthe of University Medical Center Groningen in The Netherlands, and Apostolos Papandreou of University College London in the UK.

Funded by the European Joint Program on Rare Diseases (EJP-RD) Networking Support Scheme, this pioneering initiative drew thirty participants from ten countries. Unlike traditional scientific meetings, the event was centered around interactive discussions between all participants to identify the greatest barriers to basic, translational, and clinical research for BPAN and to foster networking and resource sharing among scientists.

Discussions encompassed enrolling BPAN patient data in the TIRCON registry, seeking a BPAN biomarker essential for future clinical trials, strategies to expand the BPAN research network, increasing international collaborations and nurturing young scientists' careers.

Joost Schimmel, a board member of Stichting Ijzersterk, remarked, “Scientists are going to generate a list of available resources to study BPAN, which will accelerate our understanding of the disease, and I think this networking event could be a good starting point for a joint European grant application to study BPAN.”

NBIA Alliance Representatives: Joost Schimmel, Stichting Ijzersterk, Ovidiu Botezán, NBIA Hungary, Fatemeh Mollet, NBIA Suisse, Patricia Wood, NBIA Disorders Association, Maciej Cwyl, NBIA Poland, Amir, NBIA Suisse, Silvia Cappa, AISNAF, Serena Bertoldi, AISNAF. On screen: Top right: Amber Denton, NBIA Disorders Association, Markus Nielbock, Hoffnungsbaum, e.V., Michelle Sheppard-Whalen, NBIA Canada. Not pictured but at research meeting: Antonio Lopez, ENACH.

An official report of the workshop and a BPAN landscape analysis study is being finalized by the consulting firm Science Compass. When available, it will be disseminated to the BPAN community by the patient advocacy organizations that financed the analysis. This study will help drive future BPAN grant initiatives.

The BPAN Workshop concluded on Wednesday at 2 pm, and at 4:30 pm, representatives from CoA Therapeutics met with six NBIA Alliance members in person and others via Zoom to hear the latest update on their upcoming clinical trial set to start in 2024. Afterward, we held an Alliance meeting where each organization presented its ongoing projects, paving the way for discussions on potential research grant collaborations aligned with our common goals. An important objective on our agenda was determining the total count of NBIA families served by Alliance members without duplication while safeguarding our families' privacy. Updates to the NBIA Alliance website are also in the works.

These in-person NBIA research meetings serve as a vital platform for Alliance members to strengthen connections and reaffirm our dedication to a global NBIA community striving toward shared goals.

On Thursday and Friday, "Scientists for the NBIA Community," hosted by NBIA Poland, held its meeting featuring comprehensive scientific presentations on various NBIA disorders. The conference aimed to unite patient families, physicians and researchers to learn about the need for therapies and establish international cooperation among research centers, associations and the NBIA community.

Approximately 150 attendees were present, including families from Poland. Simultaneous translation of 22 research presentations in English or Polish meant everyone in attendance could understand all the information. Some researchers shared not-yet-published work, and the talks led to lively discussions with those in the audience, who asked many questions about the scientific information shared. There was also plenty of time for researchers and clinicians to network, discuss possible future collaborations, and share their work more informally.

After the conclusion of the meeting on Friday evening, researchers and patient organization representatives convened to further discuss topics of interest and come to a consensus on future steps. Everyone endorsed Dr. Yapici Zuhal of Istanbul University in Turkey as the host of the 9th Scientific Symposium for NBIA disorders next year.

Beyond the scientific discourse, NBIA Poland was a gracious and welcoming host, organizing a tour of The Royal Castle in Old Town, Warsaw, on Saturday, followed by a traditional Polish lunch.

It was an important week for so many in the NBIA community who came together worldwide and shared their work, ideas and friendship.

Participants at the "Scientists for the NBIA Community" meeting held in Warsaw, Poland, Oct. 19-20, 2023. NBIA Poland hosted the meeting.