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.

August 2019

A much-anticipated drug therapy has failed to show any benefit for individuals affected with PKAN, or Pantothenate Kinase-Associated Neurodegeneration, one of the most common forms of NBIA.

The drug’s maker, Retrophin Inc., announced the disappointing results Aug. 22 for its Phase 3 Fosmetpantotenate Replacement Therapy, or FORT, study.

Seventy-eight PKAN individuals had completed the 24-week randomized, double-blind study, meaning that neither the patients nor the doctors knew who was randomly selected to get the drug or the placebo. At the end of the study, 76 patients decided to participate in the open-label program in which all received the drug.

Although the drug, Fosmetpantotenate, was observed to be generally safe and well-tolerated, the study found that it did not meet its primary or secondary endpoints, or outcome measures.

First, the study found no differences between those who received the drug and those who got the placebo. That determination was based on the extent to which individuals improved over the 24-week trial, based on a scale that measures activities of daily living, such as walking, eating and dressing. Those measures were specifically adapted for PKAN individuals using Part II of the comprehensive and widely referenced Unified Parkinson’s Disease Rating Scale.

Second, the study found no measurable change on the same scale’s Part III score, which evaluates motor function, including slowness, stiffness and balance.

No data suggested that a longer course of treatment would change the outcomes, nor were any differences seen between classic and later-onset PKAN individuals taking part in the trial.

“We are very disappointed in the topline results from the FORT Study, particularly because we have seen the devastating impact of PKAN on patients and their families, and a significant unmet need remains with no approved treatment option,” said Retrophin CEO Eric Dube, Ph.D. "We would like to thank the patients, their caregivers, study investigators and our employees, whose dedication made this study possible.”

The study gathered a significant amount of data, which is still being analyzed. Retrophin plans to present its findings at scientific meetings in the fall. It also will publish the findings in a peer-reviewed journal. Company officials said they hope the data will help inform future clinical studies for treating PKAN.

August 2019

The long-awaited results from the first international clinical trial for NBIA — testing deferiprone in individuals with PKAN — are in.

They show that the iron-chelating drug slowed the progression of the disorder in older patients with a later-onset, or atypical, form of PKAN, but did not have a similar benefit for younger patients with classic PKAN, which starts in early childhood.

In addition to those findings, the study showed that the drug successfully reduced the amount of accumulated iron in the brain for PKAN individuals, regardless of onset age.

PKAN, or Pantothenate Kinase-Associated Neurodegeneration, and all other NBIA disorders share iron accumulation in the globus pallidus structure of the brain. It remains unclear, however, whether excess iron causes NBIA or is brought on by some other problem.

The results of the trial, which was funded by a European Union grant titled Treat Iron-Related Childhood-Onset Neurodegeneration, or TIRCON, were presented at the Tenth International NBIA Family Conference held May 30 to June 2 in Charleston, S.C. The findings were then published in the July issue of the medical journal, Lancet Neurology.

The lead investigator of the trial in the United States, Dr. Elliott Vichinsky of the University of California, San Francisco Benioff Children’s Hospital in Oakland, discussed the results at the conference. He said that older and younger PKAN individuals showed improvement with deferiprone in dystonia of the lower face and lower legs, as well as in cognitive functioning, especially memory. But the benefit in the younger children, who tend to have a faster-moving, more severe form of PKAN, “wasn’t statistically significant,” he said.

The 18-month trial, which ran from 2012 to 2015, involved 88 patients from the United States, Germany, Italy and England. The trial met the gold standard for research. It was randomized, with some patients getting deferiprone orally and others getting a placebo. Afterward, the trial was extended another 18 months, and the drug was made available to everyone who took part in the trial.

“The drug was well-tolerated, and the safety profile was very good,” Vichinsky told families at the conference.

But because the study did not meet a key goal — showing a statistically important improvement from deferiprone in all age groups — the U.S. Food and Drug Administration hasn’t yet approved it for PKAN. Consequently, Vichinsky encouraged interested families to contact the FDA to advocate for its approval.

To read the full article:

Published Article

To see his presentation, go to the YouTube channel for the NBIA Disorders Association conference here:

Watch Video