Neurofibromatosis Type I as a Model for Therapeutic Neuroadaptation

描述（由申请人提供）：发育性学习障碍是一种非常普遍的认知障碍形式，是一个主要的公共卫生负担，并与不良的社会后果和大量的精神病发病率相关。然而，迄今为止，还没有有效的药物治疗已经开发出这些严重致残的条件。1型神经纤维瘤病（NF 1）是了解认知障碍机制的有价值的模型，因为它是一种常见的遗传性疾病（发病率1：3000），由编码神经纤维蛋白的单个基因（Nf 1）突变引起。特殊的学习障碍是患有这种疾病的儿童最常见的神经系统并发症。该疾病的小鼠模型的开发导致了关键发现，即Ras活性增加是NF 1中学习缺陷的原因（Costa等，Nature Genet 2001）。我们最近已经证明，用HMG-CoA还原酶抑制剂洛伐他汀（作为Ras活性的有效抑制剂，通常用于治疗高胆固醇血症）治疗可以逆转在NF 1小鼠模型中观察到的生物化学、电生理学和认知缺陷（Li et al. Curr Biol. 2005）。这是第一次，这使我们能够评估遗传性疾病患者认知缺陷的药理学治疗，使用一种在临床前研究中已经验证并且有大量临床安全性数据的药物。我们现在试图将这些发现扩展到NF 1受试者的研究中，以确定是否在人类中观察到洛伐他汀治疗后大脑结构和功能的类似变化。在拟议的随机、双盲、安慰剂对照试验中，我们将使用神经认知、行为和神经生理学结局指标研究14周洛伐他汀治疗对NF 1儿童和青少年认知功能的影响。这项探索性治疗研究的结果将使我们能够建立一个更大规模的研究追求这些目标的可行性。 公共卫生相关性：1型神经纤维瘤病（NF 1）是了解认知障碍机制的有价值的单基因模型。我们的临床前研究表明，洛伐他汀治疗，通常用于治疗高胆固醇血症，可以逆转在NF 1小鼠模型中观察到的认知缺陷。在这个探索性的治疗补助金，我们建议将这些研究结果扩展到人类受试者与NF 1的研究，以确定是否类似的变化，脑结构和功能的观察后，洛伐他汀治疗人类。

DESCRIPTION (provided by applicant): Developmental learning disabilities are a highly prevalent form of cognitive impairment, which present a major public health burden and are associated with poor social outcome and substantial psychiatric morbidity. However, to date no effective pharmacologic treatments have been developed for these severely disabling conditions. Neurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of cognitive disability, as it is a common genetic disorder (incidence 1:3000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein. Specific learning disabilities are the most common neurological complication in children with this disease. The development of a mouse model of the disorder led to the key discovery that increased Ras activity is responsible for the learning deficits in NF1 (Costa et al. Nature Genet 2001). We have recently demonstrated that treatment with the HMG-CoA reductase inhibitor lovastatin, which acts as a potent inhibitor of Ras activity and is commonly used for the treatment of hypercholesterolemia, can reverse the biochemical, electrophysiological and cognitive deficits observed in a mouse model of NF1 (Li et al. Curr Biol. 2005). For the first time, this allows us to assess a pharmacologic treatment for cognitive deficits of patients with a genetic disorder, using a medication that has been validated in pre- clinical studies and for which substantial clinical safety data is available. We now seek to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans. In the proposed randomized, double-blind, placebo-controlled trial, we will study the effect of a 14-week lovastatin treatment on cognitive function of children and adolescents with NF1 using neurocognitive, behavioral, and neurophysiological outcome measures. Findings from this exploratory treatment study will allow us to establish the feasibility of a larger-scale study pursuing these aims. PUBLIC HEALTH RELEVANCE: Neurofibromatosis type 1 (NF1) is a valuable single-gene model for understanding mechanisms of cognitive disability. Our pre-clinical studies have shown that treatment with lovastatin, commonly used for treatment of hypercholesterolemia, can reverse cognitive deficits observed in a mouse model of NF1. In this exploratory treatment grant, we propose to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans.