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

Nature Medicine volume 4, pages 1261–1268 (1998)Cite this article

Abstract

As more functional redundancy in mammalian cells is discovered, enhanced expression of genes involved in alternative pathways may become an effective form of gene therapy. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid metabolism. The X-ALD gene encodes a peroxisomal membrane protein (ALDP) that is part of a small family of related peroxisomal membrane proteins. We show that 4-phenylbutyrate treatment of cells from both X-ALD patients and X-ALD knockout mice results in decreased levels of and increased β-oxidation of very-long-chain fatty acids; increased expression of the peroxisomal protein ALDRP; and induction of peroxisome proliferation. We also demonstrate that ALDP and ALDRP are functionally related, by ALDRP cDNA complementation of X-ALD fibroblasts. Finally, we demonstrate the in vivo efficacy of dietary 4-phenylbutyrate treatment through its production of a substantial reduction of very-long-chain fatty acid levels in the brain and adrenal glands of X-ALD mice.

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Figure 1: RT–PCR analysis of RNA levels in mouse (a) and human (b) primary fibroblasts before (–) and after (+) treatment with 5 mM 4PBA for 2 days.
Figure 2: a, Western blot analysis of mouse primary fibroblasts before (-) and after (+) treatment with 5 mM 4PBA for 5 days.
Figure 3: Peroxisomal ABC half-transporter complementation of C24:0 β-oxidation.
Figure 4: Peroxisomal staining in human X-ALD primary fibroblasts.
Figure 5: Peroxisome function after treatment with 4PBA.
Figure 6: RT–PCR analysis of RNA levels in mouse primary fibroblasts after 2 days of treatment with 5 mM 4PBA (a) and in human primary fibroblasts after 2 days (b) or 10 days (c) of treatment with 5 mM 4PBA.
Figure 7: In vivo efficacy of 4PBA.

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Acknowledgements

We thank H. Moser for his advice and continuing interest in this study, and S. Brusilow for discussions. We thank A. Liu, S. Wang, S. Bergin, S. Khangoora and D. Gordon for technical assistance. For review of the manuscript, we thank H. Moser, S. Brusilow, S. Gould, D. Valle and P. Zeitlin. This work was supported by grants from the National Institutes of Health, HD10981, HD24061, DK51149, and GM07814, the Myelin Project and the United Leukodystrophy Foundation.

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Authors and Affiliations

  1. Kennedy Krieger Institute; Institute of Genetic Medicine and Departments of Pediatrics and Neurology, The Johns Hopkins School of Medicine Baltimore,

    Stephan Kemp, He-Ming Wei, Jyh-Feng Lu, Lelita T Braiterman, Martina C. McGuinness, Ann B. Moser, Paul A. Watkins & Kirby D. Smith

  2. Institute of Genetic Medicine and Departments of Pediatrics and Neurology, The Johns Hopkins School of Medicine Baltimore, 707 N. Broadway, Room 400A, Baltimore , 21205, Maryland, USA

    Stephan Kemp, He-Ming Wei, Jyh-Feng Lu, Lelita T Braiterman, Martina C. McGuinness, Ann B. Moser, Paul A. Watkins & Kirby D. Smith

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Kemp, S., Wei, HM., Lu, JF. et al. Gene redundancy and pharmacological gene therapy: Implications for X-linked adrenoleukodystrophy. Nat Med 4, 1261–1268 (1998). https://doi.org/10.1038/3242

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