Scientists report on progress of current NBIA research projects

May 2018

One of the key activities of the NBIA Disorders Association is awarding research grants, most of it with money raised by our hardworking families.

The board of trustees receives invaluable help from our Scientific and Medical Advisory Board, which helps set research goals, evaluates proposals and monitors projects after the board funds them. In evaluating proposals, the advisory board puts greatest priority on new paths of study that could lead to a treatment or a cure.

Throughout the process, the advisory board follows high ethical standards. For example, researcher-advisers who submit a proposal or have a conflict of interest must state their conflict and recuse themselves from decision-making. After the board of trustees approve a grant, it holds grantees accountable for meeting deadlines, delivering the promised work and providing updates to share with families. These recipients must submit regular financial and scientific reports to our SMAB; payments are made in stages after those reports are submitted.

Since 2002, the trustees have funded 33 research grants totaling $1,290,914. The board also has funded research contracts totaling $357,408, Hayflick lab funding at $250,000 in 2009 (when it was in jeopardy of closing) and part of a clinical consensus treatment guide at $16,117. All told, that’s nearly $2 million for research.

Here are updates on recent grants the board awarded:

BPAN Mouse Model, 2015-2017

ProkischIn 2015, we awarded a $67,760, two-year grant to Dr. Holger Prokisch from Technical University Munich in Germany to create a mouse model for Beta-propellar Protein-Associated Neurodegeneration, or BPAN. This disorder, in which the WDR45 gene is impaired, is characterized by childhood developmental delays and seizures, with movement problems occurring in adulthood. WDR45 is known to be involved in autophagy, a process in which damaged cells get recycled.

This subtype of NBIA has become one of the four most common forms of NBIA.

This grant wrapped up at the end of 2017, and Prokisch shared that his lab generated a BPAN mouse model in which the WDR45 gene is impaired as it is in BPAN individuals. They also generated mice that are being investigated at the German Mouse Clinic.

“We have learned that in some aspects, the mouse model resembles the clinical presentation of the patients. This is true for impaired coordination when working on a balance beam and on the molecular level by neurodegeneration,” Prokisch said. He noted that it is important to have access to an animal model that does a good job of representing the human disease so potential therapeutic approaches can be tested.

Prokisch learned that WDR45 deficiency seems to lead to a mitochondrial dysfunction, at least in the brain. Mitochondria are important for cell energy generation and their health is essential in organs that have high-energy demand, like the brain, muscles and heart.

The lab plans to publish its findings and apply to European funders to continue this work.

In line with our organization’s information-sharing requirement for grants, comprehensive data on the mice’s characteristics (phenotype) will be available soon at the German Mouse Clinic. Online access will be available to other researchers, as well.

BPAN Neuronal Cell Model, 2014–2015

In 2014, we awarded a $44,680, one-year grant to Dr. Manju Kurian from University College London in the United Kingdom. One of the goals was to use this seed funding to develop a better neuronal model of BPAN to try and understand disease mechanisms (including their impact on cell recycling, known as autophagy), and to develop better targeted treatments for BPAN. Over the course of this 12 month grant, Dr Kurian’s team were able to generate preliminary data which allowed her team to secure longer term funding through an Action Medical Research Training Fellowship for Dr Apostolos Papandreou to undertake this important work.

In June 2016, Papandreou, a pediatric neurologist in training, attended a meeting the Oregon Health & Science University hosted for BPAN families. Papandreou is using state-of-the-art techniques to convert patient skin cells into brain cells (called neurons) to test potential therapies and determine if any might effectively combat BPAN. Some families at the OHSU meeting kindly contributed skin samples towards this study.

Papandreou also said he met several BPAN patients who provided him with valuable insight into their symptoms and care.

Using innovative research methodologies, BPAN patient skin cells have been transformed into "stem cells,” which can then be converted to cells for any bodily organ. The Kurian lab has converted stem cells into brain cells, which are the type most affected by BPAN.

Brain Cells

So far, the lab has generated stem cells from seven BPAN individuals and neurons from three. The brain cells are typical of those found in the midbrain, one of the most severely affected brain regions in BPAN. This process enables researchers to study BPAN in the right context and to compare healthy brain cells with BPAN cells.

Once the mechanisms within the cells are better understood, the London-based research group can move forward with testing thousands of drugs already available in their lab to see if any can reverse BPAN’s effects in the cells. The most effective drugs will then be ready for further testing, with the aim of using them in clinical trials.

Through experiments done in parallel, the researchers also have examined skin cells from patients with BPAN and compared them to skin cells from healthy individuals. In that way, they established that an important function of waste clearance and recycling of unwanted materials (autophagy) may be defective in BPAN skin cells.

Namely, BPAN skin cells do not seem to be able to use the built-in disposal and recycling system properly. This is in line with the early hypotheses about mechanisms causing BPAN.

“The consequences of BPAN may be that there is accumulation of toxic or harmful materials within the cells, leading to cell stress, damage and possibly early-cell death,” Papandreou said. He also suspects that this cellular function is even more important for the survival of brain cells.

BPAN brain cells need to be tested to see if the process occurs there, too. This will give more insight into how brain cells malfunction and, therefore, how symptoms, such as problems with movement and delayed development, occur in BPAN. “Moreover, if this ‘waste disposal and recycling’ cellular function is defective in BPAN brain cells, we can try and improve or correct it by treating the cells with drugs available in our lab that specifically correct this process,” he said.

The group presented a preliminary report on this work at the 6th International NBIA Disorders Symposium in Stevenson, Wash., in April 2017. Overall, the group believes they’ve made solid progress.

PKAN Mouse Model, 2014-2017

In 2012, our organization contracted with OZgene Pty Ltd. in Australia to create “Gene-targeted heterozygous mice” at a cost of $52,415. The project was completed in September 2014 with the delivery of the mice to the Oregon Health & Science University. There, Dr. Susan Hayflick’s undertook a three-year study to phenotype (document the characteristics and behaviors) these mice in the hopes of having a desperately needed good mouse model for PKAN. That contract was for $147,993.

knock-in miceThe Hayflick lab has successfully produced a knock-in mouse that contains the same mutated gene as found in classical PKAN. The group also has evaluated these animals for neurological symptoms, behavioral changes and physical differences.

The mice show some differences in behavior between female and male mice by genotype, which may warrant further analysis, but no obvious features of PKAN. However, Hayflick noted that it is not uncommon for mice to show only certain aspects of neurological symptoms or to express them differently than in humans.

Going forward, the lab hopes to analyze tissues from the animals and look for biochemical differences. The mice can also be modified to study how the PKAN mutation affects specific cells or tissues, a valuable research tool.

With the projected cost to house a mouse colony at $2,500 per month, the board decided to preserve the mice through a process called cryopreservation. This cost-saving move allows us to preserve the mice for later recovery and study. Our organization paid $1,950 for the initial cryopreservation and will pay an annual $100 fee. Re-derivation of lines is possible and interested investigators may contact us about using them.

PKAN – Possible causes of Iron Accumulation, 2015-2016

Dr. Suh Young JeongIn 2015, we funded Dr. Suh Young Jeong at the Oregon Health & Sciences University with a $45,000 study called “Mitochondrial dysfunction and hypoxia induce unused iron accumulation in PKAN.”

Jeong said that disease genes for PKAN and CoPAN are important players in the coenzyme A synthesis
pathway. Coenzyme A is a crucial factor for many essential cell functions, one of which is energy metabolism.

Using primary fibroblasts (the main connective tissue cells in the body) from PKAN patients and controls, they were able to show problems with energy metabolism, as well as diminished mitochondrial activity. Because mitochondria function as the energy factory and consumes most of the iron imported into cells, they believe this unused iron accumulates as a side effect.

Using a coenzyme A intermediate (what does intermediate mean here?), they were able to restore energy metabolism in these cells and decrease the accumulated iron. Although this problem in energy metabolism might not be the only problem caused by disrupted CoA synthesis pathway, these data suggest a potential treatment approach for PKAN and CoPAN.

”Thanks to the support from NBIADA, we were able to obtain interesting and crucial data for our projects,” Jeong said recently. “With this preliminary data, we presented at two international meetings and received useful and positive feedback.” Those presentations were at the 6th International Symposium on NBIA & Related Disorders in April 2017 in Stevenson, Wash., and the 7th Congress of the International BioIron Society in May 2017 in Los Angeles.

She added: “We were awarded with a grant from NIH and submitted two more that are currently under review, and are performing final experiments to finish our manuscript discussing cellular energy metabolism problems in PKAN. “

PKAN Best Practices, 2012-2016

In January 2012, our organization, in collaboration with AISNAF, the Italian NBIA organization, and Hoffnungsbaum e.V., the German NBIA group, contracted with the Oregon Health & Science University for a publication on best practices in the care and management of people with Pantothenate Kinase-associated Neurodegeneration (PKAN).

Each organization contributed $16,116.67 for a total cost of $48,350.01.

Demand was high for consensus, evidence-based guidelines to help clinicians and families better care for individuals with this rare disorder. Professionals with expertise working with PKAN patients were asked to contribute, along with some affected families. The guideline development also included physicians, genetic counselors, therapists and others.

Priorities were set, evidence was gathered and draft guidelines were prepared and revised. From this effort, a consensus document emerged.

We believe the guidelines will serve to support newly diagnosed individuals and their families, as well as to treating physicians. The guidelines are intended to be dynamic and will be regularly updated.

The project was completed in September 2016, and the guidelines were published in March 2017. A pdf of the publication can be found on our website at 

MPAN – Unravelling the function of C19orf12, 2014-2016

Group at Helmholtz Center in MunichIn 2014, our organization awarded Dr. Ana Messias at the Helmholtz Center in Munich, Germany, a $45,000 grant to study MPAN. The C19orf12 gene in MPAN individuals encodes a protein of unknown function that is associated with mitochondria. Messias, along with Drs. Arie Geerlof and Arcangela Iuso, wanted to understand what the protein does by studying its three-dimensional structure. The hope is that will provide insight on how the C19orf12 gene mutations lead to disease.

In this first study, the researchers came up with a preliminary structure of the C19orf protein. They showed that several MPAN mutations exhibit significant structural rearrangements and lower stability, which might help explain the impaired activity of the protein. While this original grant showed good progress, more work was needed to unravel this complicated mystery.

We awarded another $44,965 grant in 2015 to continue this important work. The researchers proposed to obtain a better structural model and use software analysis to compare the protein structure with others that have known functions.

This two-year project provided a first insight on the C19orf12 protein, how the protein is arranged three-dimensionally and the effect of known mutations on its stability and potential functionality. Messias presented her work on this project at the 6th International Symposium on NBIA & Related Disorders, April 2017, in Stevenson, Wash.

While the group achieved some important milestones and added information about the protein, no definitive answers on its function emerged. More funding is needed to carry this work forward and they are currently working on a grant application, along with preparing a first manuscript with the data obtained so far on C19orf12.

PLAN – Gene Therapy, 2014-2018

In 2014, our organization awarded $150,000 to Dr. Manju Kurian of University College London for a three-year study of a gene therapy approach for PLA2G6-Associated Neurodegeneration or PLAN. We then gave a 10 month, “no cost” grant extension so that doctoral fellow Sam Cuka could continue this work, using a University College of London Impact Grant of 34,000 pounds.

Kurian is preparing a final scientific report for our SMAB to review. She also will be providing our organization with a report we can share in our next newsletter.



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