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Updated: May 12, 2026

Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
10:30

Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy

Published on: May 24, 2016

Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy

S Kemp1, H M Wei, J F Lu

  • 1Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.

Nature Medicine
|November 11, 1998
PubMed

Insights

4-phenylbutyrate treatment effectively reduces very-long-chain fatty acids in X-linked adrenoleukodystrophy (X-ALD). This approach enhances beta-oxidation and peroxisome proliferation, showing promise for X-ALD gene therapy.

Area of Science:

  • Biochemistry
  • Genetics
  • Cell Biology

Background:

  • X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by impaired very-long-chain fatty acid (VLCFA) metabolism.
  • The X-ALD gene encodes the peroxisomal membrane protein ALDP, crucial for VLCFA metabolism.

Purpose of the Study:

  • To investigate the therapeutic potential of 4-phenylbutyrate in X-ALD.
  • To elucidate the functional relationship between ALDP and ALDRP.

Main Methods:

  • Treatment of X-ALD patient and knockout mouse cells with 4-phenylbutyrate.
  • Measurement of VLCFA levels and beta-oxidation.
  • Assessment of ALDRP expression and peroxisome proliferation.
  • Complementation studies using ALDRP cDNA.
  • In vivo studies in X-ALD mice.

Main Results:

  • 4-phenylbutyrate treatment decreased VLCFA levels and increased their beta-oxidation in X-ALD cells.
  • Treatment led to increased ALDRP expression and peroxisome proliferation.
  • ALDP and ALDRP were shown to be functionally related.
  • Dietary 4-phenylbutyrate significantly reduced VLCFA levels in the brain and adrenal glands of X-ALD mice.

Conclusions:

  • 4-phenylbutyrate is a promising therapeutic agent for X-ALD.
  • Enhanced expression of genes like ALDRP may offer a viable gene therapy strategy for peroxisomal disorders.
  • The study demonstrates the in vivo efficacy of 4-phenylbutyrate for managing VLCFA accumulation in X-ALD.

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