Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy.
ATP Binding Cassette Transporter, Subfamily D, Member 1
/ genetics
ATP-Binding Cassette Transporters
/ genetics
Adrenoleukodystrophy
/ drug therapy
Animals
Deuterium
/ metabolism
Fatty Acids
/ metabolism
Fatty Acids, Nonesterified
Inflammation
Mice
Mice, Knockout
PPAR gamma
/ metabolism
Pioglitazone
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
02
05
2022
received:
14
02
2022
accepted:
03
05
2022
pubmed:
6
5
2022
medline:
20
7
2022
entrez:
5
5
2022
Statut:
ppublish
Résumé
X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C-ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to-date for ALD. Pioglitazone, an anti-diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPARγ agonism) and nongenomic (mitochondrial pyruvate carrier-MPC, long-chain acyl-CoA synthetase 4-ACSL4, inhibition). However, its use is limited by PPARγ-driven side effects (e.g. weight gain, edema). PXL065 is a clinical-stage deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonism but retains MPC activity. Here, we show that incubation of ALD patient-derived cells (both AMN and C-ALD) and glial cells from Abcd1-null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1-null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPARγ agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.
Identifiants
pubmed: 35510808
doi: 10.1002/jimd.12510
pmc: PMC9545763
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily D, Member 1
0
ATP-Binding Cassette Transporters
0
Abcd1 protein, mouse
0
Fatty Acids
0
Fatty Acids, Nonesterified
0
PPAR gamma
0
Deuterium
AR09D82C7G
Pioglitazone
X4OV71U42S
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
832-847Subventions
Organisme : National Institute of Health, USA
ID : NS114245
Informations de copyright
© 2022 Poxel SA. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
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