NBIA NEWS & INFORMATION

June 2020

Thanks to money raised in last year’s Million Dollar Bike Ride, the NBIA Disorders Association is supporting a stem cell research project in Australia that will examine BPAN’s effects on the brain and drugs that could help treat the disorder.

Dr. Paul Lockhart of Murdoch Children’s Research Institute (MCRI) in Melbourne is leading the project and received a grant in February for $60,561 from the bike ride’s sponsoring organization, the University of Pennsylvania. Of that total, the NBIA community raised $30,561 and won the maximum match of $30,000 from the school’s Orphan Disease Center to study Beta-propeller Protein-Associated Neurodegeneration (BPAN).

Our organization was deeply involved in the grant-making process. We wrote the request for proposals, and members of our Scientific & Medical Advisory Board reviewed the applications and made recommendations. The University of Pennsylvania will manage the grant and send us a copy of the final scientific report that Lockhart’s team submits.

The project is titled “Development of novel human stem cell models of BPAN for disease modeling and drug screening,” and is being conducted by the Bruce Lefroy Centre, a genetics research unit at MCRI, where Lockhart is co-director. His co-investigators are Dr. Martin Delatycki and Dr. Jay Shukla.

BPAN families in Australia meet with researchers at the Murdoch Children’s Institute in Melbourne.

The team has identified 11 individuals in Australia who have BPAN, ranging in age from toddlers to a 36-year-old. Most of them have agreed to donate their skin cells for the study. MCRI researchers will reprogram those cells using cutting-edge stem cell technologies to generate the kind of nerve cells affected by BPAN. This ‘brain in a dish’ model allows direct testing of how BPAN affects brain function and offers a way to rapidly screen large numbers of drugs for potential treatments.

The team will create neural networks that mimics the way nerve cells communicate with each other in the human brain. They hope these models will help them identify what causes specific neurons in the brain of BPAN-affected individuals to degenerate much earlier than in individuals without the disorder. In addition, the team will use the models to test drug compounds that might be effective in treating BPAN. Such studies are required before a potential treatment can move to a clinical trial in patients.

This research is part of a larger project launched in December 2019 with an anonymous $200,000 donation in honor of five-year old Angus Hunter, who has BPAN. The Hunter family lives in Melbourne and is active in raising awareness and funds for BPAN research, as well as providing support to BPAN families.

June 2020

The NBIA Disorders Association has awarded a $45,000 research grant to a team of German scientists studying stem cells in patients with the NBIA disorder known as FAHN.

Led by Dr. Andreas Hermann, along with Drs. Moritz Frech and Jiankai Luo of the University Medical Center Rostock, the team will create a model of FAHN, or Fatty Acid Hydroxylase-associated Neurodegeneration, in the lab, along with stem cells to better understand how the disease works. With that understanding, the researchers can advance to testing potential therapies to see whether they can reverse FAHN’s effects.

The team plans to create a supply of patient-specific induced pluripotent stem cells, which have the capacity to become any cell in the body. They can also self-renew, meaning that they divide and produce more stem cells.

To develop these stem cells in the lab, cells will be taken from the connective tissue of FAHN patients. Researchers will then use a gene-editing technology, CRISPR/Cas9, to add copies of certain genes to the cells, endowing them with a stem cell’s special characteristics. They can develop into central nervous system cells that may be affected by FAHN.

The researchers will team up with Dr. Sunita Venkateswaran, an assistant professor and pediatric neurologist at the University of Ottawa. She is well established in the field of NBIA and will collaborate with the team on the research.

The project is called "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.” It is being funded from March 1, 2020, through Feb. 28, 2021.

November 2019

NBIA researchers Drs. Susan Hayflick and Penny Hogarth recently announced that, thanks to added help from a federal grant, they will soon launch a clinical trial to test a compound, CoA-Z, in individuals with PKAN, a common form of NBIA.

The grant is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health.

The CoA-Z compound will be tested in the U.S. and Canada to see if it corrects a metabolic process involved in producing coenzyme A in individuals with PKAN.

To prepare for the trial, the researchers recently did a study in a small number of PKAN adults and children who received CoA-Z under supervision at the Oregon Health & Sciences University, where the Hayflick and Hogarth Team is located. The information gained from this study was used to refine the dosing plan for the trial and help determine when blood samples should be collected.

The preliminary testing confirmed that CoA-Z was safe for PKAN individuals to take over the short period of the study.

In addition to the NIH grant that will fund the clinical trial over a period of several years, $2 million in donations has been raised from a variety of sources over the past two years to support the manufacturing and formulation of CoA-Z, database development and other costs not covered by the NIH grant. NBIA families held many fundraisers, with proceeds going to the nonprofit Spoonbill Foundation founded by Hayflick and Hogarth. Funds also came from Stichting Lepelaar, a nonprofit Drs. Ody Sibon and Hans Hektor set up in the Netherlands, the Dutch Foundation for Rare Diseases, and $50,000 from the NBIA Disorders Association.

The OHSU team led by Suh Young Jeong, PhD, in partnership with Sibon's group, recently published an article in the journal EMBO Molecular Medicine on CoA-Z, titled "4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN." The article was based on a mouse model of PKAN. The researchers say this mouse is important because it is the first to show abnormal iron accumulation in the brain, as well as other PKAN changes.

These mice did not have any dystonia, but they had biochemical changes of PKAN in the same brain region as in people with PKAN. According to the article, after taking 4'-phosphopantetheine by mouth for two weeks, all of the PKAN biochemical changes in mouse brain improved.

Researchers also tested skin cells from people with PKAN, and the same biochemical changes were found. When the cells were bathed in 4'-phosphopantetheine, the changes resolved. The mouse experiments showed that 4'-phosphopantetheine is not degraded in the gastrointestinal tract and that it can cross the blood-brain barrier.

Sibon's group published a separate paper in the same journal issue titled, "CoA-dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases," that reveals important insights into the biochemical changes in PKAN and related disorders. The researchers believe these two publications provide a solid foundation for launching studies of CoA-Z in people.

Information for this article was taken from http://nbiacure.org/coaz-clinical-trial/ where you can go for more information and updates on the clinical trial.