Advancing Molecular Diagnoses and Protein Replacement Therapies in Tooth Agenesis

 描述（由申请人提供）：牙齿发育不全，先天性缺失一颗或多颗恒牙，是人类最常见的遗传性疾病，影响高达10%的人口，即使排除第三磨牙。这种情况作为一种孤立的异常或作为数十种综合征的一部分发生，并对患者及其家人造成重大的功能，情感和经济负担。由于牙齿发育不全患者的美学和功能恢复是复杂和昂贵的，新的治疗方法是必要的。因此，一个核心的挑战是，迫切需要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能够使这些患者受益的切实可行的治疗方法。这项研究的长期目标是开发安全有效的替代疗法，以纠正人类非综合征性牙齿发育不全。我们提出了翻译的方法，将测试的假设，选择重组蛋白或小分子激活剂/抑制剂的主要发育信号通路的及时管理，将能够取代缺失或突变的基因产物所需的牙齿发育。此外，替代蛋白不必与引起牙齿发育不全的蛋白相同，因为突变基因的下游靶/效应物也可以单独或与其他下游效应物组合实现所需的效果。我们的方法的灵感来自于最近成功地使用重组Ectodysplasin A（rEDA）蛋白治疗X连锁少汗性外胚层发育不良（艾德）的小鼠和狗，结果导致临床试验，现在正在评估的安全性和有效性的rEDA治疗人类与ED。提出了三个目标如下：（1）探索扩大使用EDA治疗非综合征性牙齿发育不全。(2)开发和评估新型Wnt治疗非综合征性牙齿发育不全的方法。(3)通过人类遗传学方法鉴定新的牙齿发育不全基因。该项目解决了一个与临床高度相关的重要问题，对此没有治愈方法。来自这些转化研究的数据将提供测试这些疗法是否可用于恢复受非综合征性牙齿发育不全影响的人类的牙齿发育所需的原则的证据。从最广泛的意义上说，这项研究将影响推动其他影响颅面复合体和其他系统的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.