Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism

Hartley, Meredith D.; Shokat, Mitra D.; DeBell, Margaret J.; Banerji, Tania; Kirkemo, Lisa L.; Scanlan, Thomas S.

doi:10.1016/j.chembiol.2020.02.008

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…This set the basis for a new therapeutic strategy for X-ALD patients aiming at inducing ABCD2 expression with pharmacological, hormonal, or nutritional management [ 41 , 42 ]. Pharmacological induction of ABCD2 was indeed shown to compensate for ABCD1 defect in vitro and in rare cases, in vivo, opening the way for clinical trials [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

Section: Structure Function and Mechanism Of Transportmentioning

confidence: 99%

“…These promising results suggest that such a therapeutic strategy may be as effective as allogeneic HSCT. In addition, efforts to find pharmacological strategies targeting oxidative stress, inflammation, or compensatory mechanisms (antioxidant cocktail [ 93 ], leriglitazone [ 94 ], sobetirome [ 50 , 54 , 55 ]) are still present. It remains to be evaluated whether such treatments would be useful per se or in combination with HSCT strategies, at least to delay the onset of neurological concerns and permit a lengthening of the time window to allow transplantation.…”

Section: Human Diseasesmentioning

confidence: 99%

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Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.

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Section: Structure Function and Mechanism Of Transportmentioning

confidence: 99%

Section: Human Diseasesmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Overexpression of ABCD2 has been an approach to compensate the function loss of ABCD1. In 2017 and 2020, studies showed that upregulation of ABCD2 by thyromimetics, such as sobetirome and its prodrug in ABCD1mice significantly reduced VLCFA level in various tissues, (Hartley, Kirkemo, Banerji, & Scanlan, 2017;Hartley et al, 2020) up to 50% in peripheral tissues and 15-20% in the brain. In their studies, the ABCD1mouse model did not show serious impairment of motor functions, so it was difficult to access its effectiveness in curing X-ALD.…”

Section: Pre-clinical Studies Of X-ald For New Therapeutic Developmentmentioning

confidence: 99%

Management of adrenoleukodystrophy: From pre-clinical studies to the development of new therapies

Ma,

Li,

Zhou

et al. 2024

Preprint

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X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane protein. It results in accumulation of very long chain fatty acids in tissues and body fluid. Along with other factors such as epigenetic and environmental involvement, ABCD1 mutation-provoked disorders can present different phenotypes including cerebral adrenoleukodystrophy (cALD), Adrenomyeloneuropathy (AMN), and Addison’s disease. cALD is a life-threatening form that causes death in young children. Bone marrow transplantation and hematopoietic stem cell gene therapy are only effective when performed at an early stage of onsets in cALD. Nonetheless, current research and development of novel therapies are hampered by a lack of in-depth understanding disease pathophysiology and a lack of reliable cALD models. The ABCD1- and ABCD1-/ABCD2-/- mouse models and ABCD1- rabbit models created in our lab, do not develop cALD phenotypes observed in human being. In this review, we summarize the clinical and biochemical features of X-ALD, the progress of pre-clinical and clinical studies. Challenges and perspectives for future X-ALD studies are also discussed.

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“…A prodrug strategy that fulfills these criteria was recently developed in our lab for CNS targeting of the synthetic thyromimetic drug sobetirome. , We have used this strategy to increase sobetirome penetration into the CNS with mouse models of demyelination and lipid metabolism. , This prodrug strategy is underpinned by two pivotal processes and entails (1) converting the drug’s carboxylic acid functional group into an N -methyl amide, which imparts beneficial physicochemical properties for BBB penetration via passive diffusion. As an amide, (2) the prodrug is a substrate for fatty acid amide hydrolase (FAAH), an amidase with enriched expression in the CNS that cleaves the amide prodrug into the carboxylate-containing parent drug.…”

Section: Introductionmentioning

confidence: 99%

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

Ferrara

Scanlan

2020

J. Med. Chem.

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The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptors modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy which directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty-acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Cleavage of the prodrugs by FAAH in the CNS substantially increases brain exposure and brain-to-serum ratios (Kp), with increases up to ~100-fold compared to the Kp of the systemically administered parent drug. Structure-activity relationships reveal that drug-like molecules with a linear shape are the best FAAH substrates, and comparisons of CNS vs peripheral drug-induced pharmacodynamics validate the CNS-selective distribution. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.

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Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism

Abstract: Highlights d CNS-penetrating thyromimetic prodrug Sob-AM2 is better tolerated in chronic dosing d Sob-AM2 is more effective than sobetirome at lowering C26:0 in the CNS d VLCFA reduction in the CNS is limited by slow CNS lipid turnover

Cited by 8 publications

References 30 publications

Peroxisomal ABC Transporters: An Update

Peroxisomal ABC Transporters: An Update

Management of adrenoleukodystrophy: From pre-clinical studies to the development of new therapies

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

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