Recipient Organization
UNIV OF PENNSYLVANIA
(N/A)
PHILADELPHIA,PA 19104
Performing Department
School Of Veterinary Medicine
Non Technical Summary
Patients with defective ectodysplasin A (EDA) are affected by X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition characterized by hairlessness, inability to sweat, decreased lacrimation, frequent pulmonary infections, and missing and malformed teeth. The canine model of XLHED was used to study the developmental impact of EDA on secondary dentition, since the dog has an entirely brachyodont, diphyodont dentition similar to humans, and as opposed to mice that only have permanent teeth (monophyodont dentition). Also, clinical signs in XLHED humans and dogs are virtually identical, whereas several are missing in the murine equivalent. In our model, the genetically missing EDA was compensated for by post-natal intravenous administration of soluble recombinant EDA. Untreated XLHED dogs have an incomplete set of conically shaped teeth similar to those seen in human patients with XLHED. After treatment with EDA, significant normalization of adult teeth was achieved in 4 of 5 XLHED dogs. Moreover, treatment restored normal lacrimation and resistance to eye and airways infections, and improved sweating ability. These results not only provide a proof of concept for a potential treatment of this orphan disease, but also demonstrate an essential role of EDA in the development of secondary dentition.
Animal Health Component
75%
Research Effort Categories
Basic
25%
Applied
75%
Developmental
(N/A)
Goals / Objectives
The objective of this project is to assess the efficacy and safety of a recombinant protein in the treatment of X-linked ectodermal dysplasia caused by a defect in the ED1 gene. Treatment trials are performed in mice and dogs with the same disease as in huamns. Absorption, distribution and half life of the drugs are examined as well as the optimal time point in life at which the drug is to be administered.
Project Methods
Dogs with ectodermal dysplasia are given recombinant ectodysplasin at different doses and different time points during the neonatal period to determine the safety and efficacy of this treatment in preparation for using the drug in humans with the same condition. The safety of the drug will be determined by evaluating physical health, CBCs, serum biochemistry screens, and necropsy. The efficacy will be evaluated by determining lacrimation, mucociliary clearance, the ability to sweat, overall health and normalization of dentition.