Developing a preventive cure for cerebral palsy

描述(由申请人提供)： 在过去的十年里，围产期脑性瘫痪(CP)的发病率并没有下降，在一些西方国家甚至有所上升。社会的代价是巨大的，因为失去了潜在的社会生产性成员，给个人、家庭和社会机构带来了持续一生的直接负担。因此，CP是疾病负担指数最高的疾病之一，但在开发预防CP的方法方面却没有取得任何进展。目前还没有一种治疗方法可以帮助防止缺氧缺血后CP的发生。限制这一关键领域进展的主要问题是缺乏临床上相关的CP动物模型，缺乏足够的资源用于这一问题，以及缺乏系统的方法来解决这一问题，所有这些都在本提案中得到解决。我们将在胎盘早剥的临床范例的基础上，使用早孕急性胎盘功能不全后发展的兔CP模型。这个围产期模型是第一个可靠地导致CP的模型，因此它允许我们严格测试假定的治疗方法是否可以预防动物的CP运动缺陷。此外，我们将使用第二种非啮齿动物脑损伤动物模型，该模型与另一种范式--脐带闭塞--在胎羊上相关。这个模型允许详细的胎儿监测，评估潜在的副作用，关键的是，允许我们在第二个临床相关的大型动物模型中确认潜在的治疗是保护性的。我们还建议成立一个研究小组，利用这些健壮的动物模型来研究早产儿子宫缺氧缺血(H-I)。这个研究小组将使用一种算法来开发基于特定的、临床可重复的里程碑的新疗法。我们将首先使用明确定义的标准对八个最有希望的候选治疗方案进行优先评估。第一个目标是在早产兔模型中测试最有希望的候选药物，模拟早产胎盘减少运动障碍，类似于第二阶段临床试验。除了对母亲的安全之外，还将确定对围产期死亡和其他运动缺陷的影响。一种无效的设计将被用来选择药物以达到下一个目标。第二个目标将选择第一个目标确定的最有希望的候选者，并将在兔模型中测试它们，就像在第三阶段临床试验中一样。第三个目标将测试从第二个目标发展而来的最佳候选者，即胎儿绵羊的安全性和早产绵羊脐带闭塞模型的有效性。因此，胚胎绵羊的研究将提供基本的安全数据，例如没有观察到的不良反应水平和在人类身上无法从伦理上获得的支持性结果数据。这项R-21提案的最终目的是开发一项U01提案，以开发有前景的疗法，供FDA批准用于有急性胎盘功能不全风险的母亲的预防性治疗。因此，拟议的研究将为系统开发CP急需的疗法提供框架，从而加快这些疗法的临床应用。

DESCRIPTION (provided by applicant): Over the last decade, the incidence of cerebral palsy (CP) of perinatal origin has not been decreasing and has even increased in some Western countries. The costs to society are huge, from the loss of potential productive members of society and the direct burden on the individual, family, and social institutions that last the entire life. Thus CP has one of the very highest indices of burden of disease, and yet there has been no progress in developing ways of preventing CP. There is no therapy on the horizon that might help to prevent CP developing after hypoxia-ischemia. The major problems limiting progress in this key area are the lack of clinically relevant animal models for CP, lack of sufficient resources devoted to this problem, and a lack of a systematic approach to tackle the problem, all of which are addressed in this proposal. We will use the rabbit model of CP that develops after acute placental insufficiency at preterm gestation, based on the clinical paradigm of abruption placenta. This perinatal model is the first to reliably lead to CP, and so it allows us to rigorously test whether putative therapies can prevent the motor deficits of CP in animals. In addition, we will use a second, non-rodent animal model of brain injury related to another paradigm, umbilical cord occlusion, in fetal sheep. This model allows detailed fetal surveillance, to evaluate potential side-effects and, critically, allows us to confirm that potentially therapies are protective in a second, clinically-relevant large animal model. We also propose to form a study group that will utilize these robust animal models to study in utero hypoxia-ischemia (H-I) in the preterm fetus. This study group will use an algorithm to develop new therapies based on specific, clinically reproducible milestones. We will first prioritize the eight most promising therapeutic candidates for evaluation using well defined criteria. The first Aim will test the most promising drug candidates in a preterm rabbit model mimicking abruption placenta for reducing motor deficits analogous to a Phase II clinical trial. The effect on perinatal deaths and other locomotor deficits will also be determined in addition to safety to the mother. A futility design will be used to select drugs to go to the next Aim. The second Aim will take the most promising candidates identified by the first Aim and will test them in the rabbit model as in a Phase III clinical trial. The third aim will test the best candidates developed from the second aim for safety in fetal sheep and efficacy in a preterm sheep model of umbilical cord occlusion. The fetal sheep studies thus will provide essential safety data, such as the no observed adverse effect levels and supportive outcome data that cannot be ethically obtained in humans. The eventual aim of this R-21 proposal is to develop a U01 proposal to develop the promising therapies to consideration for FDA approval for preventive treatment in a mother at risk for acute placental insufficiency. The proposed studies will thus provide the framework for the systematic development of much-needed therapies for CP and thus expedite the clinical application of these therapies,