Dendrimer–N‐acetyl‐L‐cysteine modulates monophagocytic response in adrenoleukodystrophy

• Published in: Annals of neurology Vol. 84; no. 3; pp. 452 - 462
• Main Authors: Turk, Bela R., Nemeth, Christina L., Marx, Joel S., Tiffany, Carol, Jones, Richard, Theisen, Benjamin, Kambhampati, Siva, Ramireddy, Raj, Singh, Sarabdeep, Rosen, Melissa, Kaufman, Miriam L., Murray, Connor F., Watkins, Paul A., Kannan, Sujatha, Kannan, Rangaramanujam, Fatemi, Ali
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-09-2018
• Subjects: Acetylcysteine; Acetylcysteine - metabolism; Adrenoleukodystrophy; Adrenoleukodystrophy - genetics; Adrenoleukodystrophy - metabolism; Adult; Aged; Antioxidants; Antioxidants - metabolism; Atomic layer epitaxy; ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics; ATP-Binding Cassette Transporters - genetics; Brain - metabolism; Chains; Chemical compounds; Child; Cysteine; Demyelination; Dendrimers - metabolism; Fatty acids; Female; Glutathione; Human behavior; Humans; Immune response; Immune system; Intracellular; Macrophages; Male; Microglia; Microglia - metabolism; Middle Aged; Mutation; Neurodegenerative diseases; Patients; Pharmacology; Phenotype; Phenotypes; Stimulation; Tumor necrosis factor-α; Young Adult
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25303

Objective
X‐linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder due to mutations in the peroxisomal very long‐chain fatty acyl‐CoA transporter, ABCD1, with limited therapeutic options. ALD may manifest in a slowly progressive adrenomyeloneuropathy (AMN) phenotype, or switch to rapid inflammatory demyelinating cerebral disease (cALD), in which microglia have been shown to play a pathophysiological role. The aim of this study was to determine the role of patient phenotype in the immune response of ex vivo monophagocytic cells to stimulation, and to evaluate the efficacy of polyamidoamine dendrimer conjugated to the antioxidant precursor N‐acetyl‐cysteine (NAC) in modulating this immune response.
Methods
Human monophagocytic cells were derived from fresh whole blood, from healthy (n = 4), heterozygote carrier (n = 4), AMN (n = 7), and cALD (n = 4) patients. Cells were exposed to very long‐chain fatty acids (VLCFAs; C24:0 and C26:0) and treated with dendrimer‐NAC (D‐NAC).
Results
Ex vivo exposure to VLCFAs significantly increased tumor necrosis factor α (TNFα) and glutamate secretion from cALD patient macrophages. Additionally, a significant reduction in total intracellular glutathione was observed in cALD patient cells. D‐NAC treatment dose‐dependently reduced TNFα and glutamate secretion and replenished total intracellular glutathione levels in cALD patient macrophages, more efficiently than NAC. Similarly, D‐NAC treatment decreased glutamate secretion in AMN patient cells.
Interpretation
ALD phenotypes display unique inflammatory profiles in response to VLCFA stimulation, and therefore ex vivo monophagocytic cells may provide a novel test bed for therapeutic agents. Based on our findings, D‐NAC may be a viable therapeutic strategy for the treatment of cALD. Ann Neurol 2018;84:452–462