Advancing Molecular Diagnoses and Protein Replacement Therapies in Tooth Agenesis

 描述(申请人提供)：牙齿发育不全，即先天缺乏一颗或多颗恒牙，是人类最常见的遗传性疾病，即使排除第三颗磨牙，也会影响多达10%的人口。这种情况以孤立的异常或作为数十个综合征的一部分出现，并给患者及其家人带来重大的功能、情感和经济负担。由于恢复牙齿发育不全患者的美观和功能是复杂和昂贵的，新的治疗方法是有必要的。因此，一个核心挑战涉及将几十年来关于牙齿发育和牙齿发育不全的基础和临床研究成果转化为可使这些患者受益的切实疗法的迫切需要。这项研究的长期目标是开发安全有效的替代疗法来纠正人类非综合征性牙齿发育不全。我们提出的翻译方法将检验这样的假设，即及时给予主要发育信号通路的重组蛋白或小分子激活剂/抑制剂将能够取代牙齿发育所需的缺失或突变的基因产物。此外，替代蛋白不必与导致牙齿发育不全的蛋白相同，因为突变基因的下游靶点/效应器也可以单独或与其他下游效应器结合达到预期的效果。我们的方法是受到最近成功使用重组外胚叶发育不良A(Reda)蛋白治疗X连锁少汗性外胚层障碍(ED)小鼠和狗的启发，这些结果导致了临床试验，现在正在评估Reda治疗人类ED的安全性和有效性。提出三个目标：(1)探索EDA疗法在非综合征性牙齿发育不全治疗中的推广应用。(2)开发和评价治疗非综合征性牙齿发育不全的WNT新疗法。(3)利用人类遗传学方法寻找新的牙齿发育不全基因。该项目解决了一个临床相关性很高的重要问题，目前还没有治愈的方法。来自这些转译研究的数据将提供所需的原则证据，以测试这些疗法是否可以用于恢复受非综合征牙齿发育影响的人类的牙齿发育。在最广泛的意义上，这项研究将影响推动影响头面部复合体和其他系统的其他单基因疾病治疗领域的概念和技术。

 DESCRIPTION (provided by applicant): Tooth agenesis, the congenital absence of one or more permanent teeth, is the most common inherited disorder in humans, affecting up to 10% of the population, even when third molars are excluded. The condition occurs as an isolated anomaly or as part of dozens of syndromes and imposes significant functional, emotional and financial burdens on patients and their families. Since restoring esthetics and function for patients with tooth agenesis is complex and expensive, new therapies are warranted. Thus a central challenge relates to the critical need to translate the fruits of several decades of basic and clinical research on tooth development and tooth agenesis into tangible therapies that can benefit these patients. The long-range goals of this research are to develop replacement therapies that are safe and effective in correcting non-syndromic tooth agenesis in humans. We propose translational approaches that will test the hypotheses that the timely administration of select recombinant proteins or small molecule activators/inhibitors of major developmental signaling pathways will be able to replace missing or mutated gene products needed for tooth development. Furthermore, replacement proteins do not have to be identical with the tooth agenesis-causing protein as downstream targets/effectors of the mutated gene can also achieve the desired effect, either singly or in combination with other downstream effectors. Our approaches are inspired by the recent success in using recombinant Ectodysplasin A (rEDA) protein to treat X-linked hypohidrotic ectodermal dyslpasia (ED) in mice and dogs, results that led to clinical trials that are now assessing the safety and efficacy of rEDA therapy in humans with ED. Three aims are proposed as follows: (1) To explore the expanded use of EDA therapeutics for non-syndromic tooth agenesis. (2) To develop and evaluate novel Wnt therapeutics for non-syndromic tooth agenesis. (3) To identify new tooth agenesis genes through the use of human genetics approaches. The project addresses an important problem of high clinical relevance for which there are no cures. Data from these translational studies will provide the proof of principles needed to test whether such therapies can be used to restore tooth development in humans affected by non-syndromic tooth agenesis. In the broadest sense, this research will impact concepts and technologies that drive the field of therapies for other single gene disorders affecting the craniofacial complex and other systems.