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

Turk, Bela R.; Nemeth, Christina L.; Marx, Joel; Tiffany, Carol W.; Jones, Richard O.; Theisen, Benjamin E.; Kambhampati, Siva P.; Ramireddy, Raj; Singh, Sarabdeep; Rosen, Melissa; Kaufman, Miriam L.; Murray, Connor F.; Watkins, Paul A.; Kannan, Sujatha; Kannan, Rangaramanujam M.; Fatemi, Ali

doi:10.1002/ana.25303

Cited by 31 publications

(34 citation statements)

References 30 publications

(92 reference statements)

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“…Likewise, the 6MWT may be meaningful to monitor the clinical treatment efficacy. The observed tolerability, safety, and signs of clinical benefit of this pilot study may warrant the long-term use of these or other next-generation antioxidants [53] in a phase III, double-blind, randomized, placebocontrolled clinical trial with a larger number of subjects. The safety and tolerability of the doses used may facilitate extension of similar antioxidant combinations to other diseases that share both axonal degeneration as a significant component of clinical progression and redox imbalance as a primary or early contributing pathogenic factor [54,55].…”

Section: Discussionmentioning

confidence: 90%

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

et al. 2019

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X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260

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Section: Discussionmentioning

confidence: 90%

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

et al. 2019

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“…As with most neurologic disease, main pharmacodynamic challenges are in passing the blood–brain barrier and in the targeted delivery of a therapeutic compound. Recently, a nanoparticle polyamidoamine, PAMAM, dendrimer drug delivery platform conjugated to NAC (D‐NAC), having shown rescue of motor impairments and inflammatory status in a neonatal rabbit model of cerebral palsy (Kannan et al, ), demonstrated targeted drug delivery into Abcd1 mouse spinal cord microglia, and in ex vivo cerebral ALD peripheral blood monocytic patient cells stimulated by VLCFA (C26:0), normalization of antioxidant and inflammatory status (Turk et al, ).…”

Section: Experimental Therapeutic Trials and Strategiesmentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

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Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

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“…VLCFA stimulation of CCALD patient macrophages results in a dramatic proinflammatory response of these cells along with reduction of antioxidant capacity. 28 In addition, disruption of oxidative phosphorylation has been shown to correlate with VLCFA dose increase in ABCD1 deficiency fibroblasts. 29,30 Impaired autophagy, 31 increase in endoplasmic reticulum stress 32 and impaired endothelial tight junction functions 33 have also been observed as a consequence of VLCFA increase in ABCD1 mutant cells.…”

Section: Discussionmentioning

confidence: 99%

Drug discovery for X‐linked adrenoleukodystrophy: An unbiased screen for compounds that lower very long‐chain fatty acids

Moser

Shi

et al. 2021

J of Cellular Biochemistry

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X-linked adrenoleukodystrophy (XALD) is a genetic neurologic disorder with multiple phenotypic presentations and limited therapeutic options. The childhood cerebral phenotype (CCALD), a fatal demyelinating disorder affecting about 35% of patients, and the adult-onset adrenomyeloneuropathy (AMN), a peripheral neuropathy affecting 40%-45% of patients, are both caused by mutations in the ABCD1 gene. Both phenotypes are characterized biochemically by elevated tissue and plasma levels of saturated very long-chain fatty acids (VLCFA), and an increase in plasma cerotic acid (C26:0), along with the clinical presentation, is diagnostic. Administration of oils containing monounsaturated fatty acids, for example, Lorenzo's oil, lowers patient VLCFA levels and reduced the frequency of development of CCALD in presymptomatic boys. However, this therapy is not currently available. Hematopoietic stem cell transplant and gene therapy remain viable therapies for boys with early progressive cerebral disease. We asked whether any existing approved drugs can lower VLCFA and thus open new therapeutic possibilities for XALD. Using SV40-transformed and telomerase-immortalized skin fibroblasts from an XALD patient, we conducted an unbiased screen of a library of approved drugs and natural products for their ability to decrease VLCFA, using measurement of C26:0 in lysophosphatidyl choline (C26-LPC) by tandem mass spectrometry as the readout. While several candidate drugs were initially identified, further testing in primary fibroblast cell lines from multiple CCALD and AMN patients narrowed the list to one drug, the antihypertensive drug irbesartan. In addition to lowering C26-LPC, levels of C26:0 and C28:0 in total fibroblast lipids were reduced. The effect of irbesartan was dose dependent between 2 and 10 μM. When male XALD mice received orally administered irbesartan at a dose of 10 mg/kg/day, there was no reduction in plasma C26-LPC. However, irbesartan failed to lower mouse fibroblast C26-LPC consistently. The results of these studies indicate a potential therapeutic benefit of irbesartan in XALD that should be validated by further study.

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

Cited by 31 publications

References 30 publications

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Drug discovery for X‐linked adrenoleukodystrophy: An unbiased screen for compounds that lower very long‐chain fatty acids

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