Scientists Slow Progression of Debilitating Neurodegenerative Disorder

An international study led by scientists in Oakland and Munich, Germany, may offer hope to children and adults with a rare and debilitating genetic disorder, Pantothenate Kinase-associated neurodegeneration (PKAN), as well as a potentially new approach to treat other neurodegenerative disorders, such as Alzheimer’s, Parkinson’s disease and multiple sclerosis.

This is the first therapeutic trial in this disease and it opens up new treatments, offering hope to families suffering from this tragic neurodegenerative condition.

The study, which involved an 18-month, double-blind, placebo-controlled trial of 89 patients in the United States, Canada and Europe, found that chelating toxic levels of iron from the brain slightly slowed the progression of this often fatal genetic disorder. Findings appear June 12, 2019, in The Lancet Neurology.

“This is the first therapeutic trial in this disease and it opens up new treatments, offering hope to families suffering from this tragic neurodegenerative condition,” said Elliott Vichinsky, MD, senior author of the study, medical director for hematology/oncology at UCSF Benioff Children's Hospital Oakland, and professor at UC San Francisco. “These patients inspire me. I hope the promising results of this study will increase awareness and research for this severe genetic disease.” 

The project was initiated and led by researchers at the Ludwig-Maximilians-University of Munich and scientists at UCSF Benioff Children’s Hospital Oakland. It was carried out in the framework of TIRCON (“Treat Iron-Related Childhood-Onset Neurodegeneration”), a large collaborative project led by Thomas Klopstock, professor in the Department of Neurology, Friedrich-Baur-Institute, University of Munich, and the study’s lead author. 

PKAN is a form of neurodegeneration marked by the accumulation of iron in the brain, resulting in severe, involuntary muscle contractions, known as dystonia. It is most severe when diagnosed in infants, but is equally debilitating in adults, although deterioration is at a slower rate. Severe PKAN leads to the inability to speak, eat, control muscle twisting and contractions, and, eventually, to breathe. 

In the randomized part of the study, scientists administered the iron-chelator drug deferiprone (DFP) to 89 patients in an 18-month, double-blind, placebo-controlled trial. This was followed by “TIRCON-Extension,” an 18-month, open-label extension study in patients with PKAN.

Using MRI brain scans, the researchers found that the drug effectively removed iron from the participants’ brains over the course of the study. It also reduced the number of patients who required additional medications to control their dystonia. During the study, 21 percent of the placebo group required additional medications for dystonia, while only 11 percent of the treatment group did.

In the first half of the study, the researchers found no statistically significant difference in progression of the disease between the placebo and the chelator-treated groups. However, a closer analysis showed that a smaller subgroup of later-onset patients, with an atypical form of PKAN, had almost half the rate of disease progression when on the medication as compared to placebo. In addition, when the placebo group was switched to the drug after the first 18 months, the disease progression slowed by more than 60 percent.

“Although the clinical benefit for PKAN patients was quite limited, any slowing of disease progression in this devastating disorder is an important step,” Klopstock said. “Moreover, our study provides much insight into the natural history of PKAN which helps to shape the design of future trials in this ultra-orphan disease. The finding that brain iron can be markedly lowered by a chelator may have important implications also for age-associated neurodegenerative conditions such as Parkinson’s disease.”

PKAN/NBIA is caused by mutations in the pantothenate kinase 2 (PANK2) gene, which metabolizes neurotransmitters in the brain. The absence or abnormal function of PANK2 contributes to toxic levels of iron accumulating in the brain. While iron is essential for the body’s normal physiological function, an excessive amount is potentially toxic.

The results of this study also shed light on possible treatments for Parkinson’s disease, Alzheimer’s and multiple sclerosis, as these conditions are also associated with excess iron in the brain.

Co-Authors: The paper includes 27 co-authors from 14 institutions, including first and corresponding author Thomas Klopstock, from University of Munich. Additional co-author institutions include the Munich Cluster for Systems Neurology; ApoPharma Inc., Toronto, Canada; Neurological Institute Carlo Besta, Milan, Italy; Children’s Memorial Health Institute, Warsaw, Poland; Newcastle University, UK; Cambridge University, UK; Charles University, Prague, Czechia; University of Pècs, Hungary; Istanbul Faculty of Medicine, Turkey; and Oregon Health Sciences University, Portland, Ore. The full list of authors and affiliations can be found in the paper.

Funding: Funding was provided by the European Commission (FP7/2007–2013, HEALTH-F2–2011, grant agreement 277984, TIRCON), the US Food and Drug Administration and ApoPharma, Inc., which manufactures DFP.

Disclosures: Four co-authors (Fradette, Spino Tricta, Zhao) are employees of ApoPharma, Inc. Vichinsky and eight other collaborators report grants and/or nonfinancial support from ApoPharma, Inc. Four authors also report grants outside the submitted work from Retrophin Pharmaceuticals, which focuses on developing treatments for rare diseases, including PKAN. Full disclosures can be found in the paper.

About UCSF Benioff Children’s Hospitals: UCSF Benioff Children’s Hospitals are among the nation’s leading pediatric specialty hospitals, according to U.S. News & World Report. Their expertise includes the full range of pediatric conditions, including cancer, heart disease and neurological disorders, as well as the care of critically ill newborns. The hospital campuses, in San Francisco and Oakland, are recognized worldwide for their innovative research aimed at treating and preventing pediatric diseases. They are part of UCSF Health, whose adult hospital ranks among the top 10 medical centers nationwide. UCSF Health’s hospitals serve as the teaching hospitals for the University of California, San Francisco, a national leader in biomedical research and graduate-level health/sciences education. Visit www.ucsfhealth.org