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Therapeutic Strategies for X-Linked Adrenoleukodystrophy, a Representative Peroxisomal Disorder

  • Masashi MoritaEmail author
Chapter

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder, and is caused by dysfunction of the peroxisomal ABC protein ABCD1. X-ALD patients with the most severe phenotype display cerebral inflammatory demyelination. In X-ALD, VLCFA accumulation, a characteristic feature of all patients, is thought to be the main culprit underlying the pathogenesis. However, the mechanisms by which the VLCFA accumulated in the brain causes demyelinating neurodegeneration have not yet been elucidated. At present, hematopoietic stem cell transplantation (HSCT) at an early symptomatic state is effective in halting disease progression, thus allowing long-term survival. Therefore, early diagnosis and conduct timely transplantation are particularly important to improve the outcome of HSCT. However, HSCT is always associated with significant mortality risk and the difficulty of finding a matching donor. Recently, genetically modified hematopoietic stem cells for ex vivo gene therapy have been tested as an alternative option and are expected to eventually become standard treatment for X-ALD. In parallel, the development of therapeutic drugs that can attenuate the symptoms or maintain the asymptomatic stage for patients diagnosed with X-ALD is in progress. To date, many candidate compounds have been reported. In this chapter, we focus on the current state of HSCT and pharmacological treatments, and describe the necessity for newborn screening and the identification of predictive biological markers in X-ALD.

Keywords

ATP-binding cassette protein subfamily D1 (ABCD1) Ex vivo gene therapy X-Linked adrenoleukodystrophy (X-ALD) Newborn screening Hematopoietic stem cell transplantation (HSCT) Very long chain fatty acid (VLCFA) 

Abbreviations

ABCD1

ATP-binding cassette protein subfamily D

ACALD

Adult cerebral form

AD

Alzheimer’s disease

AdolCALD

Adolescent cerebral form

AMN

Adrenomyeloneuropathy

BBB

Blood-brain barrier

BMDM

Bone marrow-derived macrophages

CBT

Cord blood transplantation

CCALD

Childhood cerebral form

CNS

Central nervous system

ELOVL

Elongation of very long chain fatty acid

HSCT

Hematopoietic stem cell transplantation

MD

Multiple sclerosis

MRI

Magnetic resonance imaging

PBD

Peroxisome biogenesis disorder

PD

Parkinson’s disease

ROS

Reactive oxygen species

VLCFA

Very long chain fatty acid

X-ALD

X-Linked adrenoleukodystrophy

Notes

Acknowledgments

The authors thank Professor Tsuneo Imanaka for his comments and suggestions. This work was supported in part by Grants-in-Aid for Scientific Research (C) (16K09961) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Pacific Edit reviewed the manuscript prior to submission.

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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