Update on the CoA-Z clinical trial

Update on the CoA-Z clinical trial

Over the past few months, the OHSU CoA-Z study team has shared initial study results with all participants in the CoA-Z study and their families, as well as with the broader NBIA community of families, friends, clinical providers, and supporters. The following is a translation of a message from Penny Hogarth and the OHSU CoA-Z study team from NBIAcure's November newsletter: https://nbiacure.org/wp-content/uploads/2023/11/NBIAcure-Newsletter-November-2023.pdf

We had already recognized (from previous studies in PKAN mice and human samples) that 4′-phosphopanthezine ("CoA-Z") circumvents the genetic "roadblock" in vitamin B5 metabolism in PKAN. This suggests that CoA-Z will alter the progression of the disease over time. However, measuring a true change in disease progression in PKAN (or another neurological disorder) typically takes many years, so the general goals of the clinical trial were limited to finding out whether CoA-Z causes health problems or side effects, and whether it alters a certain blood level that we consider to be a good biomarker of the disease. It's important to remember that the clinical trial wasn't designed to measure a change in PKAN symptoms, at least not in a way that we were able to measure in the study.

So far, our work has focused on analyzing the data of each participant from the first six months of the study. This was the "double-blind" phase, where participants were randomly assigned to receive either a placebo or one of three different CoA-Z doses, without us knowing which group a participant belonged to. This is the best way for us to determine if the differences we are seeing are due to CoA-Z itself or if it is just a coincidence. Some of the overall results of the project are very encouraging for us:

So far, we have not seen any major health problems or side effects of CoA-Z during the study.
Perhaps most encouragingly, we are seeing a pattern in the biomarker results that strongly suggests that CoA-Z alters an important biological measure of the disease, just as we predicted. And we found that this response was dose-dependent, meaning higher doses tended to lead to a greater change in the biomarker.

In some ways, the biomarker results are the most important, because they confirm that CoA-Z acts on the central vitamin B5 processing problem in PKAN, just as we predicted. These results give us real hope that the compound will slow the progression of PKAN, although we have yet to figure out what dose is best and how early in life treatment should be started.

At the NBIA Family Meeting in May and in our follow-up communications to participants in the CoA-Z study, we mentioned the possibility of conducting one or more short follow-up studies with CoA-Z to complement our clinical trial data. After further data analysis and consideration, we have concluded that our current data is strong enough to be submitted to the FDA without additional clinical trials. If the FDA agrees, this will be the fastest path to the approvals we need to make the drug available to the PKAN community on a larger scale.

So we're leaving aside any plans for follow-up studies for now and instead focusing entirely on compiling our data that we want to submit to the FDA. That's a tall order, because it's not just about the data from the CoA-Z clinical trial, but also about all the background work that goes back to 2015: more than 500 pages! We don't have the resources to make CoA-Z more accessible before FDA approval, and so we think this is the best way to make it widely available to the PKAN community.

We know that everyone feels the urgency to make CoA-Z available. We feel it too. We also know that the community is very interested in our progress, and we will continue to keep you informed. We are pleased to have reached this point and are very grateful to the PKAN community and all of our supporters for their contributions to the CoA-Z study so far.

Translation of a message from Penny Hogarth and the OHSU CoA-Z study team, IRB Study 18782 from NBIAcure's November newsletter:
https://nbiacure.org/wp-content/uploads/2023/11/NBIAcure-Newsletter-November-2023.pdf

NBIA International Scientific Conference in Poland

NBIA International Scientific Conference in Poland

On October 19 and 20, 2023, a BPAN workshop, an NBIA Alliance meeting and an international NBIA scientific conference were held in Warsaw, Poland. Researchers, physicians and patient representatives from many countries came together to discuss research projects and results. In addition, possible new research approaches were discussed and collaborations were explored. You can read the agenda of the conference here: https://nbia-polska.org/data/files/agenda.pdf

 Participants of the conference, Image: NBIA Poland

From Hoffnungsbaum e.V. Markus Nielbock and Noah Rusch for professional reasons, unfortunately only part of the online experience. Patricia Wood of the NBIA Disorders Association (NBIA DA) was present the entire time and reported on the weekend in the NBIA DA's December newsletter:

As head of the research program at NBIA DA, I have had the privilege of participating in valuable events: a BPAN workshop, the first conference of NBIA Poland, and a meeting of the NBIA Alliance. Attending these events has proven to be very rewarding, as I have been able to witness the passion and dedication of our dedicated researchers, clinicians, and patient advocacy leaders.

The aim of the BPAN workshop was to identify and discuss possibilities for the development of therapies for beta-propeller protein-associated neurodegeneration (BPAN). The workshop was organised by our sister organisation, Stichting Ijzersterk, in collaboration with three European BPAN researchers: Rachel Wise from Ludwig-Maximilians-Universität in Germany, Mario Mauthe from University Medical Center Groningen in the Netherlands and Apostolos Papandreou from University College London in the UK.
This landmark initiative was funded by the European Joint Program on Rare Diseases (EJP-RD) Networking Support Scheme and attracted thirty participants from ten countries. Unlike traditional scientific meetings, this event focused on interactive discussions between all participants to identify the main barriers to basic, translational and clinical research on BPAN and to promote networking and sharing of resources among scientists. Discussions focused on the inclusion of BPAN patient data in the TIRCON registry, the search for a BPAN biomarker that is essential for future clinical trials, strategies to expand the BPAN research network, intensify international cooperation and promote the careers of young scientists.
Joost Schimmel, board member of Stichting Ijzersterk, noted: "The scientists will draw up a list of available resources to study BPAN, which will accelerate our understanding of the disease, and I think that this networking event could be a good starting point for a joint European funding application for research into BPAN."
An official report on the workshop and a study on BPAN landscape analysis is currently being finalised by the consultancy Science Compass. Once it is available, it will be shared with the BPAN community by the patient organisations that funded the analysis. This study will serve as a basis for future BPAN grant initiatives.

The BPAN workshop ended at 2:00 p.m. on Wednesday, and at 4:30 p.m., representatives from CoA Therapeutics met with six members of the NBIA Alliance (some of the participants were connected via Zoom) to get an update on their upcoming clinical trial, which is scheduled to begin in 2024.

This was followed by a meeting of the NBIA Alliance, where each organization presented their ongoing projects and paved the way for discussions on potential collaborations in the field of research funding aligned with our shared goals. A key objective on our agenda was to determine the total number of NBIA families served by the members of the alliance without any overlap, while maintaining family privacy. Work is also underway to update the NBIA Alliance website.
These face-to-face meetings serve as an important platform for Alliance members to strengthen connections and reaffirm our commitment to a global NBIA community that shares common goals.

On Thursday and Friday, the scientific conference "Scientists for the NBIA Community" hosted by NBIA Poland, which included comprehensive scientific presentations on various NBIA diseases. The aim of the conference was to bring together patient families, physicians and researchers to learn about the need for therapies and to build international collaboration between research centers, associations and the NBIA community.
About 150 participants were present, including families from Poland. Thanks to the simultaneous translation of 22 research presentations into English or Polish, all those present were able to understand all the information. Some researchers presented work that had not yet been published, and the presentations led to lively discussions with the audience, who asked many questions about the scientific information. There was also plenty of time for researchers and clinicians to socialize, discuss possible future collaborations, and share their work more informally.

Following the conclusion of the meeting on Friday evening, researchers and representatives of patient organisations came together to discuss further topics of interest and to reach consensus on future steps. Everyone was in favor of Dr. Yapici Zuhal from the University of Istanbul in Turkey to host the 9th Scientific Symposium on NBIA Disorders next year. Beyond the scientific discourse, NBIA Poland was a friendly and welcoming host, organizing a tour of the Royal Castle in Warsaw's Old Town on Saturday, followed by a traditional Polish lunch.
It was an important week for so many members of the NBIA community who came together from all over the world and shared their work, ideas and friendships. 

Translation of an article by Patricia Wood from the NBIA DA's December newsletter:
https://www.nbiadisorders.org/images/newsletters/NBIA_Newsletter_December_2023.pdf

The Polish patient organisation NBIA Poland thanked the participants with an open letter. The following is a German translation of the letter:

Dear guests, speakers and members of the entire NBIA community in Poland and around the world,

Following the conference "Scientists for the NBIA Community, Warsaw 2023", we would like to thank you very much for your participation, your presentations and your scientific research contributions. It is a great honour for us that you have placed your trust in us and honoured us with your presence. The scientific advances in the field of NBIA presented at the conference were impressive. We have received a lot of hope for effective treatment and an increase in knowledge to support patients. The entire NBIA community has seen wonderful, dedicated scientists, clinicians, physicians, and involved professionals working on a wide range of projects. Their hard work is both impressive and worthy of recognition. Despite many difficulties, despite so many activities, you have managed to come and stay with us. Thank you for your smile and dedication to explaining disease mechanisms, as well as for your complex research. Many of the presented results have already been presented before publication, most of them have not yet been patented or have just been achieved in your laboratories. It's very touching. It is impossible to describe the gratitude we have for you, the researchers and the entire clinical and scientific teams – it is the gratitude of the entire NBIA community in Poland and around the world. We are very proud that people like you have chosen to fight NBIA diseases, because this is the most valuable thing we could have dreamed of. They have given us hope for the progress of medicine, which is so important for patients and their relatives.

[...]
We hope you spent valuable time at our conference. We feel that the entire NBIA community has experienced a pleasant atmosphere, as well as a warm and welcoming atmosphere. Mutual support and cooperation with the goal of overcoming NBIA gives us strength that no one can take away from us. Everything we do is for our loved ones. We will try to implement and support all the findings and research proposals with the NBIA sister organizations from around the world that participated in the conference. We hope you will think of us. We invite you to Poland again, you are always welcome.
Together we can achieve more!

Board of Directors of NBIA Poland

Abridged translation of the open letter from NBIA Poland:
https://nbia-polska.org/i-konferencja

Videos of the NBIA Family Conference 2023 in the USA online

Videos of the NBIA Family Conference 2023 in the USA online

For the first time since the pandemic, the NBIA Disorders Association hosted the 12th NBIA International Family Conference in the United States. For 4 days from May 18 to 21, 2023, a total of 70 NBIA families and 41 speakers, including some NBIA experts and researchers, came together in Houston, Texas under the motto "ReUnited". The following video shows impressions of the conference. More videos and especially recordings of some very interesting lectures can be found on YouTube. With YouTube's subtitle function, German subtitles can be displayed: https://www.youtube.com/playlist?list=PLmztLyM1oP1IkOUqvjSPMH_iwgWER8VZd

In order to be able to organize an NBIA family conference in Germany as early as next year, the board of Hoffnungsbaum e.V. urgent support – please contact us!

Patricia Wood, among others, reports the following in the NBIA DA's September newsletter: The event kicked off on May 18 with clinical sessions for BPAN, PKAN, and PLAN. An opening dinner followed the same evening. A panel of experts answered pre-submitted questions in each of the clinical sessions and discussed how best to care for those affected. The MPAN families had their clinical session on Friday morning. Many of these experts were present throughout the conference, giving families the opportunity to get to know them and ask questions. The clinical sessions were attended by doctors from Houston and two doctors from Children's Hospital Torch.

Before the more intense, topic-oriented sessions began on Friday, time was set aside for a social gathering. This included time for families with a newly diagnosed loved one and for those attending the conference for the first time to learn what to expect during the weekend.

Also on Thursday and Friday, Oregon Health & Science University's NBIAcure team collected a record number of biological samples from NBIA patients, unaffected carriers, and healthy individuals for testing. These samples included skin biopsies from 35 people, as well as blood samples and dried blood stains from 102 people for the NBIA biorepository at OHSU. Volunteers from the care environment also generously donated blood and tissue to serve as part of a "control group" for future scientific studies. Allison Gregory, consultant for genetics at OHSU, said, "Control samples are hard for us to get, especially skin samples, so we're very grateful to those who made themselves available." She added: "All samples will be stored in our NBIA biorepository and used for current and future experiments. The importance of processing and storing samples like these is that we can take them out and use them years later when a new research question arises. We can also share anonymized samples with colleagues."

Image: NBIA DA

Friday was packed with sessions on general topics, followed by breakout sessions in the afternoon. Particularly popular were our disease-specific sessions, where families were able to share information, offer support to each other, and share solutions to everyday problems.

Friday's events ended with a memorial service for NBIA survivors who are no longer with us, but will never be forgotten. A violinist played, while volunteers carried a rose and called the name of a person we lost to NBIA. They placed the rose on a table decorated with candles and pictures of the deceased. The bereaved families present were asked to say a few words about their loved ones.

Saturday morning was dedicated to the latest disease-specific research results. Nineteen speakers talked about the four main NBIA disorders: BPAN, PKAN, PLAN and MPAN. Most of the talks were recorded for the public unless the researcher had information that was not yet allowed to be published.

The rest of Saturday was dedicated to fun. There was a picnic at the nearby Fire Truck Park, where we also had lunch, played games and took the conference group photo. In the evening they partied until the music stopped at 11 pm.

On Sunday morning, sessions were on the agenda for NBIA adults, siblings, and caregivers. The conference concluded with an art project designed by us, followed by a video and a slide show with the highlights of the conference.

 

Abridged translation of the original article by Patricia Wood from the NBIA DA's September newsletter:
https://www.nbiadisorders.org/images/newsletters/NBIA_Disorders_Association_September_2023_Newsletter.pdf

Insights into BPAN research at the family conference in the USA

Insights into BPAN research at the family conference in the USA

BPAN families attending the NBIA Disorders Association (NBIADA) Family Conference in Houston, Texas, in May received updates on BPAN research from four researchers.

Kira Anderson

First up was Kira Anderson, a study coordinator with the NBIAcure team at Oregon Health & Science University (OHSU), who is working with Dr. Hogarth, principal investigator of the BPANready natural history study of BPAN. The findings from this study are based on the disease progression of affected individuals and are critical to understanding how the disease progresses and when therapeutic interventions might have the best effect.

The current study involves 127 people, most of whom have already been examined for the tenth time, which illustrates the scope of the study. It was found that BPAN patients who have seizures experience them for the first time at a very early age, but that they often disappear again in adolescence or early adulthood. Another finding is that puberty can start earlier in girls with BPAN. However, menstruation usually begins at a typical age. Another finding was that 17% of girls with BPAN aged 10 years and older take Parkinson's medication, while 55% of boys in this age group do so to alleviate movement problems.

NBIADA funded this study for the first two years with a grant and funds from the Million Dollar Bike Ride. For the third year, OHSU used other funds. The NBIADA then awarded another grant for two years in 2022. This will allow five years of data to be collected to obtain quantitative results.

Dr. Mario Mauthe

Dr. Mario Mauthe, a researcher at the University of Groningen in the Netherlands, described how his team is trying to identify and repair cellular processes that are disrupted by a mutated WDR45 gene. His team's approach is to first identify the cellular processes in which WDR45 plays a role. They then want to determine their function and, in the final step, decipher how these processes can be repaired.

Their main focus is currently on a cell line called SH-SY5Y, which is derived from brain cells and in which they switch off the WDR45 protein. This allows them to mimic the processes involved in BPAN and observe how the cells differ from a control cell line that is not affected by BPAN. They can also generate SH-SY5Y cells that are more similar to neurons. This gives them more information about what is going on in the brain and nervous system of people with BPAN.

The researchers examine the cells in which the WDR45 protein is switched off to see whether autophagy functions as it should. They found that it is disrupted in these cells and cannot be corrected by conventional interventions.

Dr. Mauthe also observed a difference in the mitochondria of the cells. Compared to the healthy control cells, these cells show slower growth and lower energy. The researchers want to further investigate these cells and also cells derived from BPAN patients to determine whether they have the same problems. Their ultimate goal is to find a drug that can repair the defective processes found in BPAN patients.

Dr. Bertrand Mollereau

Dr. Bertrand Mollereau, Professor at the Laboratory of Biology and Cell Modelling in Lyon, France, discussed whether restoring autophagy to its normal function is a relevant treatment option for BPAN. After an overview of cell biology, the mechanisms of autophagy and previous studies on autophagy, he asked whether a disruption is directly responsible for other defects known in BPAN, such as impairments in iron metabolism and other cellular entities. If this is the case, it is hoped that restoring autophagy will simultaneously improve the subsequent defects.

After an overview of the animal models used to study WDR45 defects, Dr. Mollereau showed how his team has extended the use of fruit fly models (Drosophila) to study neuronal damage in BPAN.

Drosophila show degeneration, neuronal atrophy, motor impairment and reduced life expectancy. The damaged Drosophila also show reduced autophagy and iron accumulation, which has not been achieved in any animal model to date, making this model very similar to the human representation of WDR45.

Iron accumulated in the brain can damage neurons. Mollereau wanted to reproduce this process in flies. Here, too, they showed the expected reaction that the increase in iron had a damaging effect.

Dr. Mollereau and his team are in the early stages of drug testing. They are testing drugs that are known to improve autophagy in cells, drugs that target iron metabolism and drugs that restore mitochondrial function.

Lena Burbulla

Dr. Lena Burbulla from Ludwig-Maximilians-Universität in Munich spoke about the susceptibility of the dopaminergic neurons of the midbrain in BPAN and how she wants to uncover the cause of the degeneration of these special neurons. These neurons produce dopamine, which controls movement in particular. As Burbulla also conducts extensive research into Parkinson's disease, she wants to find out whether Parkinson's research can also be helpful in researching BPAN. Parkinson's and NBIA diseases, especially BPAN, share common features, such as movement disorders, parkinsonism and the accumulation of iron in the same regions of the brain.

Using Induced Pluripotent Stem Cell (iPSC) technology, the researchers have cultivated stem cells to develop specific neurons such as those of the midbrain. These cells are cultivated over hundreds of days. The researchers are studying the course of development to find out where it may be possible to intervene.

In Parkinson's disease, dopamine metabolism is disturbed and so her team wondered whether this is also the case in BPAN. Dopaminergic neurons obtained from BPAN patients using iPSC technology show a disturbed iron balance and significantly increased oxidized dopamine. This ineffectively processed dopamine is highly reactive when it comes into contact with iron in the brain, resulting in a toxic environment for the neurons. The problem could be reduced by iron chelation, lowering dopamine levels and using antioxidants.

She investigated her theory using 3D midbrain organoids, a kind of "mini-brain". These were cultivated from skin cells of BPAN patients. This enabled her to confirm that oxidized dopamine in combination with iron proved to be toxic to the 3D midbrain.

These insights into BPAN research show that collaborative efforts are opening new avenues for a deeper understanding of the complex mechanisms of BPAN and potential therapies. As this research progresses and intertwines, there is growing hope for better opportunities for all BPAN sufferers.

Translation of the original article from the September newsletter of the NBIA DA:
https://www.nbiadisorders.org/images/newsletters/NBIA_Disorders_Association_September_2023_Newsletter.pdf

MDBR sets donation record and makes 2 scholarships possible

MDBR sets donation record and makes 2 scholarships possible

The NBIA Disorders team and NBIA families raised a record amount for BPAN research this year as part of the University of Pennsylvania's Million Dollar Bike Ride (MDBR) (UPenn). More information about this charity bike race can be found here: https://www.hoffnungsbaum.de/mdbr2023/

In total, the team raised $64,188, including registration fees and $12,220 from another fundraiser. The UPenn contributed another $30,000, and another $25,814 went to the BPAN Fund because the recipient of the 2019 MDBR grant, Dr. Paul Lockhart of Melbourne, Australia, ran into trouble during the pandemic and was unable to spend that amount. So, a total of $120,000 is available for two BPAN research grants of $60,000. UPenn will administer the grants and has invited BPAN researchers to submit a unilateral letter of intent by September 15, 2023. Complete applications by invitation were due on October 16, 2023. For more information, see the call for proposals on the NBIA Disorders Association (NBIA DA) website: https://www.nbiadisorders.org/research/grants-program-funding-opportunities

As in previous years, the NBIA DA writes the application criteria and selects the reviewers. In addition, the NBIA DA will be kept informed by the researchers so that the NBIA community can be informed of the progress. The funding period runs from 1 February 2024 to 31 January 2025.

Participants of the "NBIA Disorders" team on the day of the race in Philadelphia. Image: NBIA DA

The MDBR was held both in-person and virtually, a popular pandemic-era option that allows NBIA families unable to travel to Philadelphia to attend. In total, there were 29 team members who fundraised, drove, volunteered, and encouraged others to donate for them. The volunteers of the "NBIA Disorders" team were also on duty at a rest stop with water and snacks for the cyclists.

As we celebrate the extraordinary achievement of NBIA Disorders, we also recognize the generosity of the donors and supporters who have made this success possible. Their contributions, both financial and emotional, have been instrumental in advancing research into BPAN, now the most common NBIA condition.

Slightly altered translation of the original article by Patricia Wood from the NBIA DA's September newsletter:
https://www.nbiadisorders.org/images/newsletters/NBIA_Disorders_Association_September_2023_Newsletter.pdf

BPAN researcher develops stem cell model and awaits funding for planned drug screening

BPAN researcher develops stem cell model and awaits funding for planned drug screening

Dr. Paul Lockhart of the Murdoch Children's Research Institute in Melbourne, Australia, says that while his BPAN research has developed an important "brain cell" model using stem cells from affected BPAN individuals, his next step - screening (systematic series testing) of drugs for treatment - is still awaiting adequate funding.

Dr. Paul Lockhart

Lockhart received $60,561 in February 2020 from the 2019 Million Dollar Bike Ride (MDBR) grant program, which US families have supported. He planned to conduct drug screening after his initial findings, but the pandemic led to staff shortages and much higher drug screening costs than anticipated. As a result, he returned $25,814 in unspent funds this spring. That money was added to this year's donations to the University of Pennsylvania-sponsored MDBR and will now help fund two $60,000 BPAN research grants under the current solicitation.

Lockhart says the model he developed using stem cells from BPAN patients will be used to screen 3,000 Food and Drug Administration (FDA)-approved compounds in search of a BPAN treatment. The screening process will require several years of funding to identify drugs that can restore normal cell function, known as autophagy, which is the degradation and recycling in damaged cells.

Lockhart's project was titled "Development of novel human stem cell models of BPAN for disease modeling and drug screening" and was part of a larger project that was the first research on BPAN in Australia. It was made possible by a $200,000 anonymous donation in 2019 in honor of Angus Hunter, who suffers from BPAN. The Hunters live in Melbourne and are actively involved in raising awareness and funds for BPAN research.

Lockhart's team used skin cells from six affected children. These samples were converted into induced pluripotent stem cells (iPSC), which can then be transformed into almost any type of human cell.

The team altered the gene to create an identical, matching (isogenic) iPSC that corrects the genetic change that causes BPAN. The researchers transformed these identical pairs into brain cells in a lab dish and analyzed them to determine what effects the genetic change had on cell structure and function. These biochemical studies examined how well the autophagy process worked in the mutant cells.

Lockhart, who spoke about this work at the 2021 NBIA Disorders Association Family Conference, said that a method was developed from the iPSCs to successfully generate neurons and also glial cells that essentially function normally. This showed that the genetic modification had no significant effect on the cells' ability to survive, to transform into different types of brain cells and to form the connections between cells that are critical for brain function.

In addition, analysis of autophagy metabolism showed that it was not functioning properly in the affected cells compared to control subjects. This finding confirmed that the iPSC model can reproduce what has been observed in other cell and animal models and demonstrates its usefulness as a preclinical model for understanding the effects of BPAN on brain function. Although Lockhart was unable to conduct further studies, his group was able to demonstrate that rapamycin, an FDA-approved drug, can increase autophagy activity in the model.
This preclinical "brain cell" model of BPAN is important, Lockhart says, because it "means that we can generate the brain cell types that are specifically affected in individuals with BPAN. These include cortical neurons, which are important for cognitive function, and dopaminergic neurons, which are important for movement."

Lockhart plans to publish his findings and will conduct a drug screening as soon as funding is secured.

Translation of the original article by Patricia Wood from the September NBIA DA newsletter:
https://www.nbiadisorders.org/images/newsletters/NBIA_Disorders_Association_September_2023_Newsletter.pdf

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