Iron chelation in pantothenate kinase–associated neurodegeneration: A possible new avenue for slowing down disease progression in neurodegeneration

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a rare group of hereditary neurodegenerative disorders. Pantothenate kinase–associated neurodegeneration (PKAN) accounts for approximately 50% of all NBIA cases and is caused by mutations in the PANK2 gene coding for pantothenate kinase-2 (PANK2). Reduced or absent PANK2 activity leads to excess intracellular iron deposition in the basal ganglia and ultimately to neurodegeneration. The clinical spectrum spans from severe infantile-onset generalized combined dystonia (typical PKAN) to juvenile-adult onset milder forms (atypical PKAN). In either variant the disease is inevitably progressive, leading to major disability, and disease-slowing therapy is not available. Lack of progress in therapeutic research can in part be attributed to the low prevalence of PKAN (only 1–3 per 1 million people). Thus, previous research was limited to case reports, case series, or small-sized open-label studies. With their recent study, Klopstock and colleagues took a giant leap forward toward better understanding of the natural course of PKAN subtypes and toward potential therapeutic interventions. They examined the safety and efficacy of deferiprone, an orally administered iron chelator, in 76 patients with typical or atypical PKAN in an 18-month double-blind, randomized, controlled multicenter study with an adjunctive 18-month open-label phase. Deferiprone can penetrate the blood–brain barrier, absorb intracellular excess iron, and convey it to the otherwise intact iron transportation and storage facilities, that is, transferrin and ferritin. Coprimary end points for efficacy were severity of dystonia and patient global impression of improvement. Despite a nonsignificant result in each primary end point after 18months, their effortmerits great recognition for several reasons. The study illustrates the importance of international patient registries for rare disorders to enable adequate study population sizes to perform high-quality randomized, controlled trials that advance our knowledge of these indeed orphan diseases. The study population was derived from the TIRCON database funded by the European Union to foster research in NBIA (https://tircon.eu). Successful reduction of excess brain iron was clearly demonstrated by follow-up MRI. Notably though, the degree of iron removal did not correlate with clinical improvement, underscoring the importance of early diagnosis and treatment initiation (ie, once the damage is done, reversal is not possible). However, the subgroup of the less severely affected atypical PKAN patients indeed showed less clinical deterioration with deferiprone compared with placebo, establishing a causative link between iron removal and delayed disease progression. Dysfunctional iron homeostasis is also found in other neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease and is linked to pathological protein aggregation. First small sample trials in PD with a 6-month duration showed a possible disease-modifying effect following treatment with deferiprone, and a larger trial (FAIRPARK-II) is near completion of patient recruitment (ClinicalTrials.gov identifier: NCT02655315). The most severe adverse effects under therapy with deferiprone include neutropenia and agranulocytosis which is why weekly blood counts are required. However, in studies on deferiprone in neurodegenerative disorders published to date, the incidence of agranulocytosis or neutropenia was limited to single cases, in all of which these resolved after discontinuation of deferiprone. In summary, because of its overall beneficial safety profile, iron chelation with deferiprone is an interesting candidate treatment approach to slow down disease progression in a variety of neurodegenerative disorders. The results of the trials currently underway are expected with great interest.