NBIA NEWS & INFORMATION

New $115,000 grant awarded to study possible PKAN therapy

December 2021

A Yale University professor has received a research grant worth $115,000 that could help lead to a treatment for PKAN, the second most common form of NBIA.

 

Choukri Ben Mamoun, Ph.D.,
at Yale University, receives grant
for $115,000 to study PKAN.

Choukri Ben Mamoun, Ph.D., a professor of medicine (infectious diseases) and microbial pathogenesis at Yale, won the “Best Presentation” award in Yale Lifesciences PITCHFEST 2020 for his work on a possible treatment for Pantothenate Kinase-Associated Neurodegeneration (PKAN). That award prompted three NBIA patient organizations—the NBIA Disorders Association, Hoffnungsbaum e.V., in Germany and AISNAF in Italy—to collaborate on making the grant, in August. 

Ben Mamoun also received the Blavatnik Award this year, which is awarded by the Blavatnik Fund for Innovation at Yale University to select projects after a competitive application process. The $300,000 award provides additional seed funding for the PKAN project.

The NBIA groups’ research grant to Ben Mamoun is titled “A High-Throughput Screen for PKAN Reversing Agents.” The goal is to look for small molecules that restore normal function in cells that are deficient in the PANK2 gene, which is impaired in PKAN individuals.

PANK2 directs the production of pantothenate kinase, which is involved in the execution of several essential biochemical reactions in the body. So, a drug that restores or mimics the function of the PANK2 gene could be effective in treating PKAN.

Ben Mamoun will look for small molecules to create a drug that can activate a second Pank enzyme to compensate for the loss of PANK2. The hope is such a drug could restore neurological function in PKAN individuals. The research also will evaluate the safety and efficacy of this novel treatment by conducting tests in the lab and in mouse models.

Previously, Ben Mamoun’s research focused on developing new antimicrobial compounds that do not inhibit human enzymes. Instead, Mamoun’s team discovered that their compounds not only inhibited the human enzyme but that nine of them activated it. That discovery fueled Ben Mamoun’s interest and opened up the possibility to treat PKAN by using the novel compound to activate the gene that causes PKAN.

 

 

Research expands BPAN knowledge on how iron accumulates in brain

December 2021

 

Dr. Young Ah Seo from the University of Michigan
School of Public Health in Ann Arbor, Michigan.
Work from this grant has been published in the
Journal of Neurochemistry.

Dr. Young Ah Seo’s recently completed research, “Defining the Roles of Iron in BPAN,”  has generated new information about how iron accumulates in the brains of individuals with Beta-propeller Protein-associated Neurodegeneration (BPAN), the most common form of NBIA. 

Seo, an assistant professor in the department of nutritional sciences at the University of Michigan School of Public Health in Ann Arbor, and her team, observed that the dysfunctional WDR45 gene in BPAN led to impaired iron storage in the brain, causing iron to build up to a toxic level that damages cells.

In 2018, Seo received the first-ever early-career research grant from the NBIA Disorders Association, for $150,000. Although the grant work was meant to be completed in two years, Seo received a one year, no-cost extension because of delays caused by the pandemic.

Her team’s goal was to identify the major proteins and pathways involved in iron accumulation when the WDR45 gene is deficient and how the altered iron uptake and metabolism contribute to neurodegeneration.

The WDR45 gene is involved in autophagy, a natural process that helps clear unnecessary materials from cells. Exactly how the mutated gene also leads to iron accumulation in the brain has not yet been fully understood, so Seo and her team sought to unravel the mystery.

They successfully generated a cell model of BPAN in which the WDR45 gene was deleted. They saw significantly elevated iron levels in this model, suggesting that it accurately mimicked the condition seen in individuals with BPAN.

They found that the absence of the gene’s protein, also named WDR45 (when not italicized it refers to the protein), led to significant changes in the pathways that are responsible for the uptake and regulation of iron in cells. This may be the basis of brain iron accumulation.

They also observed that the overload of iron in cells in this model was associated with impaired ferritinophagy. This is a form of autophagy that degrades a protein responsible for iron storage in cells, called ferritin. Essentially, the process that helps prevent excessive iron storage was impaired.

Finally, they observed that WDR45 deficiency led to excessive iron accumulation in the mitochondria, altered mitochondria metabolism and overproduction of toxic reactive oxygen species (unstable molecules that easily react and cause cell damage). This may contribute to the neurodegeneration seen with BPAN.

All together, these findings suggest a potential underlying cause of disease to explain how iron accumulates in BPAN. 

Seo’s work from this grant has been published in the Journal of Neurochemistry, titled “A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation”. She intends to seek new funding to expand on the project’s findings. 

 

 

Planned grant for MPAN research reflects joint effort with newly defined priorities

December 2021

The NBIA Disorders Association is teaming up with three European sister organizations to seek proposals for an MPAN research grant worth about $160,000.

Aisnaf logoThe collaborative grant-making effort has financial support from our organization, as well as AISNAF (Italy), Hoffnungsbaum e. V., (Germany) and Stichting Ijzersterk, (Netherlands). We are inviting selected researchers to submit a proposal for the Mitochondrial-membrane Protein-Associated Neurodegeneration (MPAN) study, with the aim of awarding a grant in May 2022.

Hoffnungsbaum logo.jpgThe call for proposals is the outcome of a coordinated process to identify MPAN research priorities. AISNAF, Hoffnungsbaum e.V., and our organization recognized the need for an MPAN Landscape Analysis in 2020, which is a comprehensive study of the global research done to date on MPAN. We reached this conclusion after failing to receive viable proposals in 2018 and 2019 for MPAN. We then hired Science Compass, led by Dr. Francesca Sofia, to facilitate the research review process.

Stichting logoThis included a thorough examination of the scientific literature on MPAN, NBIA, and other relevant diseases, as well as information from publicly available institutional websites and databases. Several researchers with longstanding expertise in NBIA disorders participated in interviews conducted between June and July 2020. The landscape resulting document provided a platform for discussions held during a two-day virtual workshop in October 2020. 

The workshop participants, including researchers, clinicians and patient organization representatives, identified and prioritized two key objectives for understanding and potentially treating MPAN.  

The first priority is to foster basic research that is crucial to advance our understanding of the C19orf12 gene that causes MPAN, and its associated protein. Although C19orf12 was discovered in 2011, its function and role in disease remains largely unknown. The disease accounts for approximately 5% of all NBIA cases. Between 2011 and 2019, a total of seven research projects studied MPAN, including those by our organization, NBIA Switzerland, NBIA Poland and Hoffnungsbaum e.V. But there is still much to be learned about this disease.

The second priority is to develop new disease models, both in the lab and within the patient population. Additionally, efforts must be made to investigate and categorize the range of symptoms and disease features. To date, no clinical or observational trials have been conducted on MPAN, so we lack comprehensive data describing symptoms and outcomes. Finally, researchers need to determine which tissues are likely to be affected by mutations to C19orf12.

Basic research can provide the foundation for insights with the potential for therapeutic interventions in MPAN. No drug or therapy has yet been found to modify MPAN. In theory, gene therapy offers promise, but at this stage, it is only a concept. Research may uncover the benefit of other drugs, including ones now used for other diseases.

Overall, the consensus from the roadmap highlights the need for translational research, which bridges scientists, clinicians and patients together. It allows for basic research to be more quickly translated into practical applications for patients, a priority identified in the strategic planning process.

We are hopeful that our knowledge of MPAN will grow, and that there will be help for MPAN families who have been waiting for years to see a breakthrough in research and potential treatments.

 

 

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