NBIA NEWS & INFORMATION

Researchers working on FAHN research at the University Medical Center Rostock. L-R Dr. Jan Lukas, Dr. Moritz Frech, Fatima Efendic, and Dr. Andreas Hermann.

A team of German scientists who won a $45,000 research grant from the NBIA Disorders Association in 2020 has successfully produced a stem cell model of FAHN, which researchers can use to better understand the disorder and test potential therapies for this disease.

FAHN, or Fatty Acid Hydroxylase-associated Neurodegeneration, is a rare form of NBIA. The type of stem cell the researchers produced is an induced
pluripotent stem cell, which can be programmed to develop into any type of human cell.

The team developed the stem cells from skin fibroblasts from FAHN patients. This tissue contained copies of the mutated FA2H gene that causes the disease. The special ability of a stem cell to turn into any type of cell in the
body now allows the researchers to generate central nervous system cells affected by FAHN.

The team was led by Dr. Andreas Hermann, along with Dr. Moritz Frech, Dr. Jan Lukas and PhD student Fatima Efendic, of the University Medical Center Rostock. They teamed up with Dr. Sunita Venkateswaran from the University of Ottawa. She provided the skin fibroblast cell lines for the research. 

The research was titled “In vitro disease modeling of Fatty Acid Hydroxylase-associated Neurodegeneration (FAHN): Patient specific induced pluripotent stem cells and their neuronal derivatives as human models of FAHN.”

The COVID-19 pandemic caused delays in completing the work, which is ongoing. Third-party funding through the Center for Transdisciplinary Neuroscience Rostock at the University Medical Center in Rostock, Germany, will allow the project to continue through April 2023.

Researchers plan to create additional induced pluripotent stem cell lines, each carrying different disease-relevant mutations. One focus is establishing protocols for differentiation of these cells into oligodendrocytes. Oligodendrocytes generate the myelin sheath in the central nervous system, which surrounds the nerve cell axons and thus ensures rapid signal transmission. Because degeneration of the myelin sheath occurs in FAHN patients, the team aims to investigate the causes of these disorders of the myelin sheath using the newly established model system.

With a better understanding of the abnormal changes in cell functions that occur during disease progression, the researchers can advance to testing potential therapies to see whether they can reverse FAHN’s effects.

A published paper on the work, “Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg,” is available online. Latest results of the project will be presented at the 8th International Symposium on NBIA, taking place from October 13th to 15th, 2022, in Lausanne, Switzerland.

September 2022

By Vanessa Smith

For the sixth year in a row, NBIA families came together for the Million Dollar Bike Ride and raised more than enough to win a significant matching grant to advance BPAN research.

Team NBIA raised $38,735 from supporters, plus $1,040 in registration fees, for a total of $39,775 and won a $30,000 match from the University of Pennsylvania’s Orphan Disease Center. That will enable the NBIA Disorders Association to offer a $69,775 BPAN research award in the 2022 UPenn grant call now underway.

Interested researchers have until Sept. 16 to submit letters of intent, with full applications by invitation due by Oct. 17. More information and links to upload letters of intent can be found here.

Like previous Million Dollar Bike Ride awards, UPenn’s Orphan Disease Center will manage the BPAN research grant, with our organization writing the application criteria and selecting the grant reviewers. The funding period runs from Feb. 1, 2023, to Jan. 31, 2024.

Volunteers Yiota and John Anastasiasis with Kristi Florio and her children manning a rest stop at the MDBR.

For the first time in three years, the ride was held in person, in addition to retaining a virtual aspect that began in 2020 because of the pandemic. For the in-person competition June 11,18 riders representing Team NBIA Disorders gathered at UPenn, along with volunteers Kristi Florio of Boalsburg, Pennsylvania, and John and Yiota Anastasiadis of Andover, Maryland. The volunteers manned a rest stop, handing out water and snacks to cyclists.

Virtual participants rode in their own towns, allowing for many more NBIA families to participate than would have otherwise been possible. There also was a virtual spin class June 6 as another way to take part.

The association’s sister organization in Germany, Hoffnungsbaum e. V., participated virtually for the third year, contributing $4,867 toward the total.

German participants Noah Rusch and his family have a fundraiser for the second year benefitting the MDBR. Noah's son Laurin has BPAN.

Matt and Julie Ritzman of Oakland, California, riding at the MDBR in Philadelphia on June 11.

Matt Ritzman, chair of the NBIA Disorders Association board and an avid cyclist, participated in person with his wife, Julie Ritzman. Their daughter, Josie, has an ultra-rare form of NBIA known as PLAN.

They traveled from Oakland, California, to UPenn, choosing to ride the longest route, 70 miles, through the rolling hills of the Pennsylvania countryside. After two virtual rides, they said they were excited to finally be able to ride in person, with other participants. "It filled me with joy and excitement that is harder to manufacture when riding around my neighborhood at home," Matt said.

He felt that overall it was a fantastic ride with nice weather, wonderful volunteers, and an amazing sense of community. He shared that he was inspired to see so many NBIA families taking part.

Jennifer and Sophia Sanchez participated virtually in the MDBR by riding in their neighborhood.

Virtual riders representing the NBIA Disorders Association also said they enjoyed the experience. One of them, Sophia Sanchez, a 16-year-old with BPAN from Houston, has been riding her adaptive bike with assistance from her mother, Jennifer Sanchez, for the past seven years. When the chance came to take part in an activity she loves to fight against BPAN, they took action, logging 26 miles divided into 2-mile increments.

With each step I took and each revolution of the crank arm and pedals, we delivered a powerful blow right in the face of BPAN,” Jennifer said, “I never felt so empowered, and I was so happy Sophia and I were doing this together!” 

Tiffany Smith of Shelby, North Carolina, participating on June 6 in the MDBR virtual spin class.

Another virtual rider, Tiffany Smith of Shelby, North Carolina, rode on her stationary bike and attended the spin class. She spoke of her passion to ride in honor of her 4-year-old daughter, Georgia, who has BPAN.

 “This girl is the reason I ride, and advocate, and research, and fight, and smile,” Smith said. “She has changed my whole world and I’ll do anything in my power to help her have a better chance at a better quality of life. Without these funds being raised, we can’t move forward towards treatment, towards relief, towards a cure.”

Team NBIA Disorders riders and their families that made it to the MDBR 7 a.m. photo opportunity on ride day.

September 2022

Dr. Penelope Hogarth of the Oregon Health & Science University in Portland, receives two years of funding totaling $103,292 for BPANready

The NBIA Disorders Association is continuing to collaborate with Dr. Penelope Hogarth on research to better understand BPAN and how it affects individuals over time. Our organization recently signed an agreement with Hogarth, a movement disorders neurologist at the Oregon Health & Science University, to carry on her work for another two years at a total cost of $103,292.

BPANready, as the study is called, collects data on how the disease evolves over time (natural history). The agreement runs from March 1, 2022, to February 28, 2024, at which time BPANready will have five years of data.

Clinical information, as well as blood and other biologic samples are collected from BPAN individuals and studied immediately in the OHSU laboratory. The samples are being used to identify potential biomarkers and create a BPAN biobank for future research by investigators worldwide. That information is de-identified to protect patient privacy.

The work includes gathering medical records on BPAN individuals, using questionnaires to collect natural history information and a custom rating scale developed to determine disease progression. Participants enter information from home every six months and have blood drawn once a year.

The study will attempt to answer critical questions about BPAN, such as why one person with the disorder has severe neurological problems while another may only be mildly affected. Hogarth also hopes to find out whether deterioration typically seen later in the disease is inevitable and whether it's possible to predict the age at which regression may appear.

Allison Gregory, a genetic counselor at OHSU, works closely with Dr. Hogarth on the BPANready study.

The goal is to get the BPAN community ready for future clinical trials. Researchers hope to identify BPAN disease markers – symptoms or measurements that happen reliably in a disease, changes that predictably appear with disease progression, and symptoms that improve with treatment. A disease marker could be an MRI finding, a protein level in the blood or a rating scale to measure symptoms or function. Natural history studies provide data that serve as the foundation for future drug trials.

The NBIA Disorders Association funded the first two years of the study with $45,000 and another of $50,507 in collaboration with the Orphan Disease Center at UPenn as part of the 2017 Million Dollar Bike Ride. The third year carried on without our funding, and this new allocation will enable the completion of five years of data, at which point data analysis can be performed to get statistically relevant data. A publication on the natural history study including the data set analysis is planned, and will provide important information for future BPAN clinical trials.

Hogarth’s colleague, Allison Gregory at OHSU, said, “There are currently 140 individuals enrolled in BPANready, which is a really impressive number. The high number may be because many young children with general symptoms like developmental delay or seizures started to be referred for whole exome genetic testing on a wider basis.” OHSU has been seeing about one new BPAN person per week for some time.

“This experience with very young kids has taught us how important the BPANready study is. Since we first found the gene in a group of adults, we really had no idea what it looked like in children or toddlers,” Gregory said. “Now, through the study, we are able to follow very young children over time to better understand their development and symptoms.

“We know it can be a grind for families to complete a study visit online every six months, “ she added, “but we believe it will pay off when potential interventions are ready to go to trial since the study is helping us develop biomarkers and identify the best outcome measures.”

To learn more about the study or enroll, visit https://nbiacure.org/our-research/in-the-clinic/bpanready.

April 2022

By Patricia Wood

San Francisco-based CoA Therapeutics reports that it has successfully completed the Phase I study of healthy volunteers for a potential drug compound for Pantothenate Kinase-Associated Neurodegeneration (PKAN).

The Phase 1 trial of BBP 671 examined the safety, tolerability and effects of the drug on healthy volunteers, such as absorption rate, effect on metabolism, how it is excreted and how it is distributed throughout the body. The goal was to not only assess the drug’s safety but to determine a suitable dose and identify any potential problems before advancing to testing in PKAN individuals.

The company will present its findings at the 4th Pan American Parkinson’s Disease and Movement Disorders Congress, May 26 to 28, in Miami, Florida. CoA Therapeutics also will share study results later this year with our community, in addition to informing other scientists, clinicians and companies working on PKAN therapies.

The NBIA Disorders Association and several other NBIA patient organizations helped CoA Therapeutics develop an anonymous survey of PKAN individuals for assessing the compound’s effects when it moves to testing in affected individuals. Survey participants gave feedback on cognitive abilities, physical limitations, performance of daily activities and impact of travel. In all, 183 surveys from 23 countries were completed. Based on that feedback, the company decided to use the drug in small tablet form for the PKAN trial. (You can read a summary of the survey results here).

CoA Therapeutics says the company is focused on two activities this year: improving the formulation of compound BBP-671 and getting feedback on the clinical trial design from regulators in the European Union (European Medicines Agency) and the United States (Food and Drug Administration). Company officials will meet with regulatory authorities later this year and hope to have clinical sites open in the US and Europe by mid-2023. Anna Wade, vice-president of operations said, “We appreciate that time is of the essence for individuals with PKAN and their families, and we are moving as fast as possible.”

April 2022

Dr. Young Ah Seo from the University of Michigan School of Public Health in Ann Arbor, Michigan.

A University of Michigan researcher was awarded a new grant to continue her work into seeking potential treatments for BPAN, now the most common form of NBIA.

Dr. Young-Ah Seo received a one-year grant of $66,366 from the annual Million Dollar Bike Ride. Money raised by NBIA families and friends was matched up to $30,000 by the University of Pennsylvania Orphan Disease Center.

“The overall goal of this project is to develop new therapeutic strategies that can reduce brain iron overload and iron-induced neurodegeneration in BPAN patients,” Seo says. “We previously identified that a naturally occurring small molecule is exceptionally effective at promoting iron mobilization.”

The goal now is to use cell models derived from BPAN individuals to test whether that small molecule can be used to stave off the damage the disorder causes.

Seo completed a study in August 2021, “Defining the Roles of Iron in BPAN,” after receiving a first-ever early-career research grant from the NBIA Disorders Association for $150,000 in 2018.

That study’s objective was to identify the key proteins and pathways that are associated with the brain’s iron accumulation when the WDR45 gene is deficient in individuals with Beta-propeller protein-associated neurodegeneration. The study also examined how neurodegeneration is affected by the altered iron uptake and metabolism.

Seo’s team created a cell model of BPAN without the WDR45 gene, which showed increased levels of iron, suggesting it accurately reflected the condition seen in individuals with BPAN.

Additionally, they observed that the accumulation of iron within the model was linked to an impairment in the process that aims to prevent a dangerous amount of iron from being stored in the brain. Lastly, the deficiency in the WDR45 gene’s protein led to an excess of iron in the mitochondria, altered the mitochondrial metabolism and caused overproduction of toxic reactive oxygen species, which are highly reactive molecules that can lead to cell damage.

The findings of the first study have been published in the Journal of Neurochemistry, titled "A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation."

Seo’s Million Dollar Bike Ride-funded research, titled “Reversing Brain Iron Overload in BPAN by a Natural Small Molecule,” continues the work of the prior grant and aims to develop new therapeutic strategies that can reduce the iron accumulation in the brain and the resulting neurodegeneration in patients with BPAN.

Seo says that she is “very happy to be awarded the BPAN grant,” and is “looking forward to working on this project.” She also says that she plans to apply for a federal grant from the National Institutes of Health to further that research. First, however, she says she needs to wait on “more preliminary data from BPAN animal models as well as the preliminary data from this new grant.”