Vorantreiben der PKAN-Gentherapie: eine gemeinschaftliche Initiative

Vorantreiben der PKAN-Gentherapie: eine gemeinschaftliche Initiative

Die Erforschung einer Gentherapie für Pantothenat-Kinase-assoziierten Neurodegeneration (PKAN) schreitet dank des Engagements erfahrener Forscher und neu gegründeter Partnerschaften weiter voran.

Im Jahr 2019 wurde ein bedeutender Schritt in der PKAN-Forschung gemacht, als die NBIA Disorders Association in Zusammenarbeit mit den NBIA-Schwesterorganisationen AISNAF (Italien) und Hoffnungsbaum e.V. (Deutschland) Dr. Lauriel Earley an der University of North Carolina – Chapel Hill eine Anschubfinanzierung gewährte, um die Gentherapieforschung einzuleiten. Wissenschaftliche Unternehmungen sind jedoch oft unerwarteten Veränderungen unterworfen.

Earleys Entscheidung, ihre Arbeit an PKAN einzustellen, machte einen nahtlosen Übergang zu Dr. Susan Hayflick an der Oregon Health & Science University (OHSU) erforderlich. Hayflick hat sich 2019 bereit erklärt, die Leitung zu übernehmen. Sie bringt einen reichen Erfahrungsschatz und ein großes Engagement für die Förderung der PKAN-Forschung mit. Dr. Suh Young Jeong, Hayflicks wissenschaftliche Teamleiterin seit 2014, konnte das Projekt mit vielversprechenden Ergebnissen zu Ende führen.

Der Wechsel des Projektleiters hat der PKAN-Gentherapie weiterhin Leben eingehaucht.

Vor kurzem wurde Hayflick von der Loving Loic Foundation kontaktiert, einer gemeinnützigen Stiftung, die von Sherine und Mark Blackford zu Ehren ihres an PKAN erkrankten Sohnes Loic gegründet wurde. Die Blackfords waren persönlich an der Weiterentwicklung der Gentherapie interessiert und boten ihre Unterstützung an.

Die Loving Loic Foundation vermittelte den Kontakt zu Dr. Miguel Sena-Esteves und Dr. Heather Gray-Edwards am Horae Gene Therapy Center an der UMass Chan Medical School (UMass). Sena-Esteves, ein Experte für die Entwicklung von Gentherapien auf der Basis von Adeno-assoziierten Viren (AAV), und Gray-Edwards, eine Expertin für die Verwendung von Tiermodellen zum besseren Verständnis des Krankheitsverlaufs, erklärten sich bereit, mit Hayflicks Team zusammenzuarbeiten. Darüber hinaus wurde Dr. Penelope Hogarth von der OHSU in das Team aufgenommen, die jahrelange Erfahrung mit PKAN und Expertise in der Planung klinischer Studien mitbringt. Zum Team der klinischen Studie gehören auch Allison Gregory, genetische Beraterin, Dr. Jenny Wilson, Kinderneurologin, und Alison Freed, Koordinatorin der klinischen Forschung.

Aus den jüngsten Fortschrittsberichten geht hervor, dass das Team das Gentherapeutikum umgestaltet, um seine therapeutische Wirkung zu optimieren. An der PKAN-Mauskolonie, die das OHSU-Team in den letzten zwei Jahrzehnten entwickelt hat, wird es mehrere neu gestaltete Produkte testen, um festzustellen, welches am besten wirkt. Dieser aufwändige Prozess wird voraussichtlich mindestens zwei Jahre in Anspruch nehmen, je nachdem, was die amerikanische Gesundheitsbehörde FDA (Food and Drug Administration) dazu sagt.

Während diese kritischen Experimente laufen, wird auch hart an der Gestaltung und Vorbereitung der klinischen Studie gearbeitet. Regelmäßige Treffen mit der FDA sind in jeder Phase des Prozesses unerlässlich. Rückmeldungen und Vorschläge der FDA können sich auf den Zeitplan des Fortschritts auswirken. Derzeit weiß das Team noch nicht, wann die klinische Studie für die PKAN-Gentherapie beginnen wird, aber es spürt ebenso wie die Menschen in der PKAN-Familiengemeinschaft die Dringlichkeit.

Während die Forscher im Labor große Fortschritte machen, spielt die Loving Loic Foundation weiterhin eine entscheidende Rolle bei der Unterstützung dieses gemeinsamen Vorhabens, indem sie entscheidende finanzielle Unterstützung und Lobbyarbeit leistet. Kürzlich erhielt sie einen Zuschuss in Höhe von 21.000 Dollar, wodurch sich der Gesamtbetrag der Spenden auf 182.036 Dollar (einschließlich Sachspenden) erhöht hat, um das Projektziel von 5 Millionen Dollar zu erreichen. Wenn Sie mehr erfahren, Spenden sammeln oder zu diesem Projekt beitragen möchten, besuchen Sie lovingloic.org oder kontaktieren Sie Sherine Blackford unter info@lovingloic.org.

Übersetzung eines Artikels aus dem Newsletter der NBIA Disorders Association vom März 2024
https://nbiadisorders.org/news-events/nbia-newsletters/

NBIAcure bereitet Antrag auf FDA-Zulassung für CoA-Z vor

NBIAcure bereitet Antrag auf FDA-Zulassung für CoA-Z vor

NBIAcure, ein Forschungsteam unter der Leitung von Dr. Susan Hayflick und Dr. Penny Hogarth, das an der Oregon Health & Science University (OHSU) angesiedelt ist, hat der Gemeinschaft der Pantothenat-Kinase-assoziierten Neurodegeneration (PKAN) ein wichtiges Update bezüglich des Status von CoA-Z, einem Vitamin-Zwischenprodukt, gegeben. Im Januar gab das Team seine Entscheidung bekannt, sich auf der Grundlage der gesammelten Daten an die US-Arzneimittelbehörde (FDA) zu wenden, anstatt weitere Studien durchzuführen.

Die FDA wird die Daten der klinischen Studie auswerten, um die Sicherheit und Verträglichkeit von CoA-Z und seine Wirkung auf die Veränderung eines biologischen PKAN-Markers im Blut zu beurteilen. Die Ergebnisse der Studie deuten darauf hin, dass CoA-Z den Biomarker im Blut dosisabhängig verändert, wobei höhere Dosen eine stärkere Reaktion bewirken.

Ein wichtiges Ergebnis der Studie ist der Nachweis der Sicherheit von CoA-Z. Dazu muss festgestellt werden, dass mögliche Nebenwirkungen gleich häufig auftreten, unabhängig davon, ob die Teilnehmer ein Placebo oder eine der drei Dosen erhalten haben.
Die ersten sechs Monate der Studie wurden doppelblind und placebokontrolliert durchgeführt, um den strengsten wissenschaftlichen Anforderungen zu genügen. Dieser Ansatz zeigt der FDA, dass die Forschung mit größtmöglicher Integrität durchgeführt wurde, um mögliche Verzerrungen zu vermeiden. Die Analyse dieser Phase bestätigte die Sicherheit und Verträglichkeit von CoA-Z in allen getesteten Dosierungen.
Das Team stellt den Bericht für diese Phase zusammen mit anderen wichtigen Informationen fertig, darunter der Herstellungsprozess, die Stabilität unter verschiedenen Bedingungen und die Auswirkungen auf Tiermodelle. Ziel ist es, bis Ende März einen Antragsentwurf bei der FDA einzureichen, was auch weiterhin planmäßig verläuft.

Dr. Penelope Hogarth und Dr. Susan Hayflick
NBIAcure Oregon Health & Science Universität
Portland, Oregon

Obwohl der genaue Zeitplan für die Prüfung des Entwurfs durch die FDA noch ungewiss ist, hat die Behörde angedeutet, dass die Durchführung einer vorläufigen Bewertung vor der endgültigen Einreichung künftige Verzögerungen minimieren könnte. Das Team wird sich für eine beschleunigte Prüfung einsetzen und gleichzeitig die Zeit und Aufmerksamkeit schätzen, die dem Prüfungsverfahren gewidmet wird. In der Zwischenzeit wird sich der Schwerpunkt auf die Analyse der Daten aus dem offenen Studienteil verlagern, bei dem alle Teilnehmer die gleiche Dosis CoA-Z erhielten, um sie in den endgültigen Antrag aufzunehmen.
Im Februar stellte Dr. Penelope Hogarth, Mitglied des NBIAcure-Teams an der OHSU, die Ergebnisse der klinischen Studie auf dem 8. internationalen Symposium für pädiatrische Bewegungsstörungen in Barcelona, Spanien, vor. Zahlreiche PKAN-Spezialisten nahmen an dem Symposium teil und äußerten sich begeistert über die Ergebnisse.
NBIAcure und die Partner der Spoonbill Foundation sind zuversichtlich, dass die vorgelegten Daten ausreichen werden, um die FDA davon zu überzeugen, dass zusätzliche Studien nicht notwendig sind. Das Team bedankt sich bei der PKAN-Gemeinschaft für ihre Unterstützung und Ermutigung während dieses Prozesses.

Angepasste Übersetzung eines Artikels von Amber Denton aus dem Newsletter der NBIA Disorders Association vom März 2024
https://nbiadisorders.org/news-events/nbia-newsletters/

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

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

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

Subscribe to our Hoffnungsbaum newsletter!

With our newsletter e-mails you will receive valuable information about NBIA. If you would like to receive additional information on individual NBIA variants or special information for researchers/clinicians in addition to the general newsletter, please click here: Subscribe to additional information

Privacy policy

You have successfully registered!

*Mandatory information, you can unsubscribe from this service at any time.