New therapies for neurodegeneration
Neurodegeneration with brain iron accumulation (NBIA) is a group of rare inherited neurodegenerative diseases that are characterised by high levels of iron in the brain. The most common form of NBIA, is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the pantothenate kinase 2 (PANK2) gene. Most NBIA patients present with symptoms early in childhood and progress rapidly. Currently, there is no proven therapy to stop PKAN or any other form of NBIA. Biochemical targeting of PANK2 is emerging as an attractive approach for preventing the aberrant accumulation of the toxic N-pantothenoyl-cysteine and pantetheine in the brain. Scientists on the EU-funded TIRCON (Treat iron-related childhood-onset neurodegeneration) project wished to address this urgent and unmet need for NBIA therapy. In this context, they brought together worldwide expertise in the field, and through the TIRCON collaborative plan, they set out to pursue preclinical development of promising drugs. TIRCON activities were designed to address the rarity of the disease, the lack of patient registries and the fragmentation of research worldwide. For this purpose, they established an internationally harmonised registry of 281 NBIA patients. This database was accompanied by an international biomaterial bank from 216 NBIA patients and 372 controls. The collected material was used for genomic, proteomic, transcriptomic and metabolomic analyses towards novel disease biomarkers. They conducted a placebo-controlled, randomised clinical trial of 89 patients to establish the safety and efficacy of the iron-chelating drug deferiprone in PKAN. The study duration per patient was 18 months, during which researchers evaluated the symptomatic as well as neuroprotective effects of the drug. Additional compounds were synthesised and investigated for their capacity to rescue PKAN in cell, fly and mouse models. One of these compounds (CAB1803) was patented and promoted for application as an orphan drug. The TIRCON initiative, apart from fundamental knowledge into disease pathogenesis, succeeded at structuring the NBIA research and healthcare community at an international level. Importantly, the identified compounds could serve as novel therapies for a progressive, disabling and life-threatening disease.
Keywords
Neurodegeneration, NBIA, PKAN, deferiprone, CAB1803, patent
