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Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases

Gene Therapy volume 11, pages 1290–1295 (2004)Cite this article

Abstract

A major challenge to the concept of gene therapy for dominant disorders is the silencing or repairing of the mutant allele. Supplementation therapy is an alternative approach that aims to bypass the defective gene by inducing the expression of another gene, with similar function but not susceptible to the disrupting effect of the mutant one. Epidermolysis bullosa simplex (EBS) is a genetic skin fragility disorder caused by mutations in the genes for keratins K5 or K14, the intermediate filaments present in the basal cells of the epidermis. Keratin diseases are nearly all dominant in their inheritance. In cultured keratinocytes, mutant keratin renders cells more sensitive to a variety of stress stimuli such as osmotic shock, heat shock or scratch wounding. Using a ‘severe’ disease cell culture model system, we demonstrate reversion towards wild-type responses to stress after transfection with human desmin, an intermediate filament protein normally expressed in muscle cells. Such a supplementation therapy approach could be widely applicable to patients with related individual mutations and would avoid some of the financial obstacles to gene therapy for rare diseases.

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Acknowledgements

This work was supported by the Dystrophic Epidermolysis Bullosa Research Association (DEBRA) (LANE3 to EBL, supporting MD), Cancer Research UK (C26/A1461 to EBL, supporting SMM, RMP and PHO) and the Wellcome Trust (055090 to EBL, supporting ML). We are grateful to G Nolan and co-workers, and to P Marinkovich, for introducing us to the retroviral vector and packaging cells and providing us with stocks, and to Dan Gibbs for the initial discussions that led to these experiments.

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  1. Cancer Research UK Cell Structure Research Group, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dundee, Scotland, UK

    M D'Alessandro, S M Morley, P H Ogden, M Liovic, R M Porter & E B Lane

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  1. M D'Alessandro
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  2. S M Morley
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  3. P H Ogden
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  4. M Liovic
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  5. R M Porter
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  6. E B Lane
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D'Alessandro, M., Morley, S., Ogden, P. et al. Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases. Gene Ther 11, 1290–1295 (2004). https://doi.org/10.1038/sj.gt.3302301

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