BPAN research project funded: Iron and neurodegeneration

BPAN research project funded: Iron and neurodegeneration

In 2019, our Italian sister organization AISNAF once again led an international call for proposals for BPAN research. This was concluded at the end of July with the funding of a new research project on BPAN. Thanks to the joint efforts of AISNAF, Hoffnungsbaum (HoBa, Germany) and the NBIA Disorders Association (NBIA DA, USA) and following a two-stage evaluation by scientists and patient representatives, the project presented by researcher Lena Burbulla achieved a unanimous consensus and will now receive 65,000 euros in funding for a period of 18 months.

The goal of Burbulla, a professor at Northwestern University of Chicago (Illinois, USA), is to define the mechanisms that lead to the development and progression of BPAN, with a focus on the role of iron in the disease. All of this is based on solid preliminary data showing how loss of function of the WIPI4/WDR45 protein mutated in BPAN patients results in cells being unable to degrade iron-containing macromolecules and organelles, reducing their recycling.

Iron is an essential element of cellular life, but its level needs to be finely tuned as "free" iron is very reactive and can be potentially destructive. "When it enters the cells, iron is incorporated into the mitochondria, the cellular power plants, or stored by special proteins called ferritins. Mitochondria and ferritins are therefore the iron-rich cellular macromolecules: They can be broken down by autophagy and release iron, making it bioavailable," explains Burbulla. The scientist's innovative hypothesis is based on the idea that the pathogenesis of BPAN is not so much due to an accumulation of iron, but to a deficit of bioavailable iron, which the cells need to function properly. To test this hypothesis, Burbulla has planned a series of experiments on neurons produced from the so-called induced pluripotent stem cells (iPSC) obtained from small skin samples of BPAN patients. The advantage of this technique is that the causes of the disease can be detected directly in the diseased cells, but without invasive procedures. Once the mechanisms that cause the accumulation of unusable iron on the one hand and the lack of bioavailable iron on the other have been identified, Burbulla and his team want to test new therapeutic approaches using innovative technologies such as three-dimensional brain organoids that mimic in the laboratory what happens in the areas of the brain that are most affected in BPAN patients.

This study will lay the foundations for identifying potential therapeutic targets for the future development of a cure for BPAN. However, it will also be important to improve the understanding of the relationship between iron and neurodegeneration, which can also be applied to other forms of NBIA.

PKAN: Results of clinical trial with deferiprone

PKAN: Results of clinical trial with deferiprone

Von 2011 – 2015 wurde das internationale NBIA-Forschungsprojekt TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration) von der Europäischen Union finanziell gefördert. Ein wesentliches TIRCON-Teilprojekt war eine Klinische Studie zur Untersuchung der Sicherheit und Wirksamkeit des Eisenchelators Deferipron bei PKAN-Patienten. Diese Studie bestand aus zwei Schritten:

  1. einer randomisierten, doppelblinden,Placebo-kontrollierten Studie von 18 Monaten pro Patient (pP)
  2. einer anschließenden 18-monatigen (pP) offenen Verlängerungsstudie für vorherige Studienteilnehmer.

Es gab vier klinische TIRCON-Zentren in Deutschland, Italien,England und den USA.

Daten von bis zu 88 Patienten im placebo-kontrollierten Teil der Studie und von bis zu 62 Patienten in der Verlängerungsstudie konnten ausgewertet werden. Mit der letzten Patientenvisite Mitte März 2018 war die insgesamt über drei Jahre laufende zweistufige Studie abgeschlossen.

Deferipron wurde überwiegend gut vertragen. Zu den Deferipron-spezifischen Nebenwirkungen gehörten u.a. eine milde bis mäßige Anämie, leicht erniedrigtes Serum-Ferritin und ein leichter Eisenmangel. Dies konnte während der Studie mit Eisenergänzungsmitteln behandelt werden.

Bei 40 Patienten wurden im ersten Teil der Studie die Eisenkonzentrationen im Globus Pallidus mit MRT untersucht.Während sich diese in der Gruppe der Patienten mit Placebo nicht änderten, nahm die Eisenmenge in der Deferiprone-Gruppe deutlich ab.

Für die klinischen Untersuchungen wurden verschiedene Skalen zur Messung von Veränderungen im Studienverlauf eingesetzt. Die Barry-Albright-Dystonie-Skala stellte den primären Endpunkt dar. Hinzu kamen als sekundäre Endpunkte u.a. Skalen zur Erfassung von Parkinson-Symptomen und von Faktoren wie funktionaler Selbständigkeit oder Lebensqualität.

Obwohl während der Studiendauer bei allen Patienten die Erkrankung weiter voranschritt, ergab die Studie insgesamt Hinweise darauf, dass Deferipron –im Gegensatz zum Placebo- bei PKAN-Patienten das Fortschreiten der Erkrankung höchstwahrscheinlich verzögern kann, insbesondere, wenn man nicht nur den primären Endpunkt, die BAD-Skala, betrachtet, sondern auch die sekundären Endpunkte der anderen Skalen miteinbezieht.

Diese verzögernde Auswirkung des Eisenchelators auf den klinischen Verlauf wurde mit größerer Deutlichkeit in der Untergruppe von Patienten mit atypischer PKAN beobachtet und anschließend in der Verlängerungsstudie bestätigt. Bei Patienten, die im randomisierten Teil der Studie Placebo erhalten hatten, verzögerte sich dann der Krankheitsverlauf in der Verlängerungsstudie im Vergleich zu den ersten 18 Monaten unter Placebo. Der mögliche positive Effekt von Deferipron kam auch darin zum Ausdruck, dass Patienten, die das Medikament einnahmen, z.T. ihre übliche Dystonie-Medikation reduzieren konnten.

In die Studie waren zahlreiche Patienten mit bereits weit fortgeschrittener PKAN eingeschlossen. Mit zunehmender Neurodegeneration sinkt jedoch der zu erwartende positive Effekt von Medikamenten. Daher ist für die Zukunft zu erwägen, ob nicht ein früherer Einsatz von Deferipron, wenn noch weniger durch das Eisen verursachte Schäden vorliegen, die positive Wirkung im Sinne einer Verlangsamung des Krankheitsverlaufs verstärken könnte.

Wer mehr über die Studie erfahren möchte, findet bei The Lancet Neurology die Zusammenfassung des englischen Originalartikels. Leider steht der vollständige Artikel nicht kostenlos online im Open Access zur Verfügung. Interessenten können sich für weitere Informationen zum Artikel aber gern an info@hoffnungsbaum.de wenden.

Charity campaign "Together strong for Maya" for MPAN research

Charity campaign "Together strong for Maya" for MPAN research

A large charity event was held in Lauterbach on June 1, 2019. The fate of 12-year-old Maya, who is suffering from the NBIA variant MPAN, moves the whole town, many other people in Saarland and beyond. They all want to help Maya and her fellow sufferers with MPAN and so many donations have already been collected. Of course, the best help is an effective therapy that stops the severe course of the disease. But such a therapy does not yet exist. This requires extensive and time-consuming further research.

This is because there are major research deficits at MPAN because too few researchers worldwide are working on it, the financial resources for the implementation of sustainable, promising MPAN projects have not yet been sufficient and, in particular, essential findings from basic research are still missing to achieve a breakthrough.
Stephanie Matthiesen, Maya's mother, reports in moving words about the great willingness of the people in her region to help: "Edeltraud Closen from Gasthaus zum Warndt did not know our Maya personally at first. And yet, with the great support of the comrades of the Lauterbach volunteer fire brigade, she and her team have put together a charity festival for Maya within just under 2 months, which is second to none: including road closure, huge raffle with great prizes from fantastic sponsors and great performances throughout the day. Food and drink were well taken care of and the children were able to let off steam on the bouncy castle and on a fire ladder as well as stacking boxes. An unbelievable number of people were there and everyone helped with all their commitment and celebrated exuberantly. Every hug, every kind word and every smile has done us good. We are very grateful for that."

"The proceeds of the event are total madness," she adds. "More than 19,000 euros have been raised for research through this festival. With this amount from the festival and the money we continue to generate, we have been able to reach the incredible donation amount of more than 120,000 euros so far. This fills us with hope that MPAN research will receive a boost and a lasting boost as a result. We would like to thank all our donors."

Hoffnungsbaum e.V. makes every effort to ensure that the funds now available for MPAN research are used for quality-tested research projects as soon as possible. Projects are needed that can elucidate the underlying disease mechanisms in MPAN, identify potential treatment options or test the efficacy and safety of new therapeutic approaches in clinical trials. The money collected in the fundraiser will make a substantial contribution to this.

MPAN can also be inherited in an autosomal dominant manner

MPAN can also be inherited in an autosomal dominant manner

The NBIA research group of Dr. Susan Hayflick at Oregon Health & Science University in Portland (OR, USA) has discovered that mitochondrial membrane protein-associated neurodegeneration (MPAN) can also be inherited in an autosomal dominant manner. MPAN is one of the four most common NBIA variants and is caused by mutations in the gene C19orf12. Until now, it was assumed that the disease is inherited exclusively in an autosomal recessive manner. This means that there must be 2 mutations to trigger the disease, one each from the father and the mother. In a new publication, however, Hayflick and her team show that there are also a number of MPAN patients in whom a mutation alone can trigger the disease with the symptoms typical of MPAN. It was also possible to detect isolated mutations that were not inherited but had new occurrences in the patients, so-called de novo mutations.

Implications for diagnostics and genetic counseling

These research findings have implications for the diagnosis and genetic counseling of MPAN patients and their families. If a single MPAN mutation is detected in a patient with clinical symptoms of MPAN, the treating physician must consider autosomal dominant MPAN in the differential diagnosis. According to the authors of the article, the respective genotype can often provide information about whether a single mutation is sufficient to trigger the disease. Since MPAN can only occur in adulthood, the latest findings are of considerable importance for those affected by dominant MPAN. Your children are at increased risk of developing the disease as well.

 

Bibliographic information for the article:
Gregory A, Lotia M, Jeong SY, Fox R, Zhen D, Sanford L, Hamada J,
Jahic A, Beetz C, Freed A, Kurian MA, Cullup T, van der Weijden MCM, Nguyen V, Setthavongsack N, Garcia D, Krajbich V, Pham T, Woltjer R, George BP, Minks KQ, Paciorkowski AR, Hogarth P, Jankovic J, Hayflick SJ. Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). Mol Genet Genomic Med. 2019 May 13;:e736.

Here is the link to the Pubmed abstract:
https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&dopt=Abstract&db=PubMed&list_uids=31087512 

Here is the link to the full article:
https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.736

Financing of a second PKAN project following the 2018 call

Financing of a second PKAN project following the 2018 call

Dario Finazzi and his team at the University of Brescia are supported for their research on PKAN zebrafish by AISNAF, Hoffnungsbaum e.V. and NBIA Disorders Association for their research on PKAN zebrafish. As part of the 2018 joint international funding initiative, the project on PKAN gene therapy presented by Lauriel Earley was deemed worthy of funding by the Scientific Advisory Board and the Advisory Board of Lay Experts and received full funding of 40,000 euros.
However, of the eight projects submitted in the same category, one other project also made a positive impression on the reviewers. AISNAF, Hoffnungsbaum e.V. and the NBIA Disorders Association succeeded in providing additional funding of €22,000 for Professor Dario Finazzi's project.

The topic is "Understanding and curing PKAN: Further developments for the phenotypic rescue of a zebrafish model".

The project was launched in May 2019. Its originality lies in the use of a small but particularly advantageous animal model, the so-called zebrafish. This is a freshwater fish whose embryos develop outside the mother and are transparent, which facilitates observation and handling. Finazzi and his colleagues had previously created zebrafish with PANK2 mutations and described clear changes in the nervous and vascular systems, including edema and bleeding. Now the researchers propose to complete the analysis and focus on the assessment of coenzyme A (CoA), mitochondria and motor activity, all altered elements in PKAN.

Another important aspect of the project is research into the molecular basis of defects in the circulatory system, the development of blood vessels and the cells that form them. The data obtained will be of great importance for the identification of new molecular targets to counteract the development and progression of PKAN. Another important aspect will be the development of a rapid and reliable system for the systematic testing of molecules with therapeutic potential. "These preliminary data are essential to obtain further funding for large-scale screening of potential therapeutic agents," says Finazzi, adding, "I think this is an exciting time for PKAN researchers, for patients and their families, because we have established a solid foundation for potential care and the goals are closer than ever."

Source: https://www.aisnaf.org/news/

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