Objective: The objective of this review is to open a discussion on the usefulness of the use of cell models derived from patients as a tool valuable for the development of precision medicine in PKAN and other neurodegenerative diseases such as ataxias, chorea, multiple sclerosis and ALS

Background: Neurodegeneration with brain iron accumulation (is a group of rare neurodegenerative disorders characterized by Progressive extrapyramidal dysfunction (rigidity, choreoathetosis, neuropsychiatric disorders and iron accumulation in the basal ganglia The most common form of NACH is pantothenate kinase-associated neurodegeneration (associated with a defect in the gene for the enzyme pantothenate kinase (PANK 2 which is essential for synthesis of coenzyme A CoA

Method: We have recently described that dermal fibroblasts obtained from patients with PANK 2 mutations can manifest the main changes pathological conditions of the disease, such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction, and increased pronounced oxidative stress markers Below we assess the response to different treatments in their ability to eliminate iron and improve pathophysiological alterations in cells derived from patients (fibroblasts and neuronal cells) doi 10.4103/1673-5374.251203

Results: The treatment of fibroblasts with pantothenate in certain mutations corrects the pathophysiological alterations and eliminates the accumulation of iron and lipofuscin by stabilizing the enzyme PANK 2 The same result was obtained in neuronal cells obtained by direct reprogramming. Currently we have identified 16 commercial drugs and their combinations with positive responses at the cellular level

Conclusion: Fibroblasts and induced neurons derived from patients may provide a useful tool to identify responding PANK 2 mutations to pantothenate Similar strategies are being developed in other neurodegenerative diseases, such as ataxias, dementias, choreas, multiple sclerosis and ALS. evaluation of personalized treatments at the cellular level as well as the examination of their effect on pathophysiological changes, can help to improve the strategies therapies in them and their potential clinical use In addition, these cell models will be useful to test the efficacy of new therapeutic options in the future.

PRESENTED AT THE LXXII ANNUAL MEETING OF NEUROLOGY

References: Álvarez Córdoba M, et al, Pantothenate rescues iron accumulation in PKAN Neurobiol 2 Di Meo I, et al, Classification and molecular pathogenesis of NBIA Eur J Paediatr Neurol 2018 22 272 284 3 Konig J et al Mitochondrial contribution to lipofuscin formation Redox Biol 2017 11 673 681 4 Campanella A, et al Skin fibroblasts from PKAN patients show altered cellular oxidative status and have defective iron handling properties Hum Mol Genet 2012 Sep 15 21 18 4049 59

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MDS Abstracts - https://www.mdsabstracts.org/abstract/precision-medicine-in-neurodegeneration-associated-with-pantothenate-kinase-pkan-its-possible/