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Permanent correction of an inherited ectodermal dysplasia with recombinant EDA

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a genetic disorder characterized by absence or deficient function of hair, teeth and sweat glands1. Affected children may experience life-threatening high fever resulting from reduced ability to sweat2. Mice with the Tabby phenotype share many symptoms with human XLHED patients because both phenotypes are caused by mutations of the syntenic ectodysplasin A gene (Eda) on the X chromosome3,4. Two main splice variants of Eda, encoding EDA1 and EDA2, engage the tumor necrosis factor (TNF) family receptors EDAR and XEDAR, respectively5. The EDA1 protein, acting through EDAR, is essential for proper formation of skin appendages; the functions of EDA2 and XEDAR are not known. EDA1 must be proteolytically processed to a soluble form to be active6,7,8,9. Here, we show that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescues the Tabby phenotype in the offspring. Notably, sweat glands can also be induced by EDA1 after birth. This is the first example of a developmental genetic defect that can be permanently corrected by short-term treatment with a recombinant protein.

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Figure 1: Features and receptor binding specificity of Fc:EDA1 and Fc:EDA2.
Figure 2: In utero exposure to Fc:EDA1 results in reversion of the Tabby phenotype.
Figure 3: Time-dependent restoration of sweat glands and tail hair in Fc:EDA1-treated Tabby mice.

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Acknowledgements

We thank J. Tschopp for support; E. Säuberli and G. Badic for assistance with histology; and H. Everett, M. Mikkola and J. Zonana for helpful comments. This work was supported by grants from the Swiss National Science Foundation and the National Center of Competence in Research.

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Correspondence to Pascal Schneider.

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The method and results presented in this manuscript have been the basis of a patent application. This patent application has already been out-licensed by the University of Lausanne to a private company (Apoxis, Epalinges, Switzerland). The conditions and terms have been fixed and approved in a definitive manner. They will not and cannot be modified, whether this manuscript is accepted for publication or not.

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Gaide, O., Schneider, P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 9, 614–618 (2003). https://doi.org/10.1038/nm861

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