Prenatal Therapy in Developmental Disorders: Drug Targeting via Intra-Amniotic Injection to Treat X-Linked Hypohidrotic Ectodermal Dysplasia

Hermes, Katharina; Schneider, Pascal; Krieg, Peter; Dang, AnhThu; Huttner, Kenneth; Schneider, Holm

doi:10.1038/jid.2014.264

Cited by 39 publications

(42 citation statements)

References 12 publications

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“…Although ultrasound technologies can diagnose cleft palate conditions as early as 13 weeks of gestation, small-molecule therapies delivered in low doses to pregnant mothers are likely to be fraught with difficulties and will require further experimentation on risk-to-benefit ratios. Alternate strategies to reduce exposure of the mother could include delivery into the amniotic fluid, as shown to be effective for the delivery of recombinant ectodysplasin (Hermes et al, 2014). Alternatively, early postnatal interventions that utilize the well-timed local delivery of Wnt agonist small molecules or proteins during surgical correction procedures might prove effective in bringing about the timely closure of palatal shelves.…”

Section: The Correction Of Pax9 Mutant Palatal Defects With Wnt Agonimentioning

confidence: 99%

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

et al. 2017

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Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including and , proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis, while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders.

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Section: The Correction Of Pax9 Mutant Palatal Defects With Wnt Agonimentioning

confidence: 99%

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

et al. 2017

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“…Furthermore, intra-amniotic injections of recombinant EDA-A1 to pregnant mice partially improved the phenotype of the X-linked hypohidrotic ED newborn mice. [ 10 ] Recombinant EDA-A1 at present is in Phase-II clinical trials and is being administered to newborn males with hypohidrotic ED to hopefully alleviate some of their symptoms.…”

Section: Discussionmentioning

confidence: 99%

A case report of hypohidrotic ectodermal dysplasia: A mini-review with latest updates

Meshram

Kaur

Hura

2018

J Family Med Prim Care

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Ectodermal dysplasia (ED) is a rare hereditary disorder involving two or more of the ectodermal structures, which include the skin, hair, nails, teeth, and sweat glands. The two most common forms of the disease are hypohidrotic/anhidrotic ED and hidrotic ED. They are caused by the mutations of several genes. We present a case of a 9-year-old child with hypohidrotic ED, who presented with hypodontia, dyshidrosis, hypotrichosis, and raised body temperature. We treated the raised body temperature symptomatically with cooling techniques and antipyretics. A multidisciplinary approach with physicians from several fields is required to provide comprehensive medical care to patients with ED.

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“…Although ultrasound technologies can diagnose cleft palate conditions as early as 13 weeks of gestation, small-molecule therapies delivered in low doses to pregnant mothers are likely to be fraught with difficulties and will require further experimentation on risk to benefit ratios. Alternate strategies to reduce exposure of the mother could include delivery into the amniotic fluid as shown to be effective for the delivery of recombinant ectodysplasin (Hermes et al, 2014). Alternatively, early postnatal interventions that utilize the well-timed local delivery of Wnt agonist small-molecules or proteins during surgical correction procedures may prove effective in bringing about the timely closure of palatal shelves.…”

Section: Discussionmentioning

confidence: 99%

The Pax9/Wnt pathway regulates secondary palate formation in mice

Jia

Zhou

Fanelli

et al. 2017

Preprint

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Clefts of the palate and/or lip arise in about 1/700 human live births and are caused by multiple genetic and environmental factors. Studies of mouse knockout models of cleft palate have improved our understanding of the molecular control of palatogenesis. While it is known that Pax9 regulates palatogenesis through Bmp, Fgf and Shh signaling, there is still much to learn about its precise relationship with other pathways. Here we show that alterations of Wnt expression and decreased Wnt activity in Pax9-/- palatal shelves are a result of Pax9’s ability to directly bind and repress the promoters of Dkk1 and Dkk2, proteins that antagonize Wnt signaling. The delivery of small-molecule Dkk inhibitors (Wnt agonists) into the tail-veins of pregnant Pax9+/- mice from E10.5 to E14.5 restored Wnt signaling, promoted cell proliferation, bone formation and restored the fusion of palatal shelves in Pax9-/- embryos. In contrast, other organ defects in Pax9 mutants were not corrected. These data uncover a unique molecular relationship between Pax9 and Wnt genes in palatogenesis and offer a new approach for treating cleft palates in humans.Summary StatementThese studies demonstrate that the Pax9/Wnt genes regulate murine palatogenesis. This unique molecular relationship is proven by the correction of cleft defects in Pax9-deficient mice through Wnt agonist therapies.

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Prenatal Therapy in Developmental Disorders: Drug Targeting via Intra-Amniotic Injection to Treat X-Linked Hypohidrotic Ectodermal Dysplasia

Cited by 39 publications

References 12 publications

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

A case report of hypohidrotic ectodermal dysplasia: A mini-review with latest updates

The Pax9/Wnt pathway regulates secondary palate formation in mice

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