Future developments in XLHED treatment approaches.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common genetic disorder of ectoderm development, presenting with abnormalities of skin, teeth, hair, and secretory glands. In the first years of life, XLHED-affected patients are at risk for life-threatening hyperthermia and pulmonary infection. Survival into childhood and beyond is associated with severe dental abnormalities as well as chronic growth, respiratory, skin, eye, and psychosocial disorders. Currently there are no approved therapies to restore function in disorders of development like XLHED. Over the last two decades, molecular research has provided convincing evidence that alterations in the ectodysplasin (EDA) gene that disrupt the encoded protein EDA-A1 are causative for XLHED. In mouse and dog XLHED models, administration of a single course of an EDA-A1 replacement protein (EDI200) resulted in permanent correction of the key phenotypic features, providing the first hope for an effective, targeted therapy. Animal models for genetic disorders have their strengths and limitations that must be considered when modeling clinical studies in human patients. Of greatest significance in the case of a developmental disorder may be the relative timeline for normal development and the maturation level at birth. With FDA clearance to start EDI200 studies in XLHED patients, we are on the verge of converting a decade of animal studies into the first test of a novel paradigm for rescue and permanent correction of a human developmental disorder.