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Research ArticleSpecial Issue on Drug Delivery Technologies

Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia Using Recombinant Ectodysplasin in a Canine Model

Carol A. Margolis, Pascal Schneider, Kenneth Huttner, Neil Kirby, Timothy P. Houser, Lee Wildman, Gary L. Grove, Holm Schneider and Margret L. Casal
Journal of Pharmacology and Experimental Therapeutics September 2019, 370 (3) 806-813; DOI: https://doi.org/10.1124/jpet.118.256040
Carol A. Margolis
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Pascal Schneider
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Kenneth Huttner
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Neil Kirby
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Timothy P. Houser
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Lee Wildman
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Gary L. Grove
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Holm Schneider
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Margret L. Casal
University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania (C.A.M., M.L.C.); Department of Biochemistry, University of Lausanne, Lausanne, Switzerland (P.S.); Edimer Pharmaceuticals, Cambridge, Massachusetts (K.H., N.K.); cyberDERM, Inc., Broomall, Pennsylvania (T.P.H., L.W., G.L.G.); and Universitätsklinikum Erlangen, Kinder- und Jugendklinik, Erlangen, Germany (H.S.)
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Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.

Footnotes

    • Received December 20, 2018.
    • Accepted April 8, 2019.
  • This work was supported and funded by the National Foundation for Ectodermal Dysplasias, Edimer Pharmaceuticals, and the National Institutes of Health, Office of the Director [OD 010939]. P.S. is supported by grants from the Swiss National Science Foundation [310030_156961; 310030A_176256]. P.S. and N.K. are shareholders of Edimer Pharmaceuticals. N.K. was an employee of Edimer at the time the experiments were performed. H.S. has received research funding from Edimer Pharmaceuticals and EspeRare foundation. P.S. and H.S. are holders of patents related to the topic.

  • https://doi.org/10.1124/jpet.118.256040.

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 370 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 370, Issue 3
1 Sep 2019
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Research ArticleSpecial Issue on Drug Delivery Technologies

Fetal Therapy of Canine XLHED with Recombinant Ectodysplasin

Carol A. Margolis, Pascal Schneider, Kenneth Huttner, Neil Kirby, Timothy P. Houser, Lee Wildman, Gary L. Grove, Holm Schneider and Margret L. Casal
Journal of Pharmacology and Experimental Therapeutics September 1, 2019, 370 (3) 806-813; DOI: https://doi.org/10.1124/jpet.118.256040

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Research ArticleSpecial Issue on Drug Delivery Technologies

Fetal Therapy of Canine XLHED with Recombinant Ectodysplasin

Carol A. Margolis, Pascal Schneider, Kenneth Huttner, Neil Kirby, Timothy P. Houser, Lee Wildman, Gary L. Grove, Holm Schneider and Margret L. Casal
Journal of Pharmacology and Experimental Therapeutics September 1, 2019, 370 (3) 806-813; DOI: https://doi.org/10.1124/jpet.118.256040
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