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，是一种主要的公共卫生负担，并与不良的社会后果和严重的精神疾病有关。然而，到目前为止，还没有针对这些严重致残性疾病开发出有效的药物治疗方法。1型神经纤维瘤病(NF1)是一种常见的遗传性疾病(发病率为1：3000)，由编码神经纤维素蛋白的单基因(NF1)突变引起，因此是了解认知障碍机制的一个有价值的模型。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。这种疾病的小鼠模型的发展导致了一个关键发现，即RAS活性增加是NF1学习障碍的原因(Costa等人。《自然基因》2001)。我们最近已经证明，HMG-CoA还原酶抑制剂洛伐他汀是RAS活性的有效抑制剂，通常用于治疗高胆固醇血症，可以逆转在NF1小鼠模型中观察到的生化、电生理和认知障碍(Li等人。Curr Biol.2005)。这使我们第一次能够使用一种已经在临床前研究中得到验证并且有大量临床安全性数据的药物，来评估一种针对遗传性疾病患者认知缺陷的药物治疗。我们现在试图将这些发现扩展到对患有NF1的人类受试者的研究，以确定在人类接受洛伐他汀治疗后是否观察到类似的脑结构和功能变化。在拟议的随机、双盲、安慰剂对照试验中，我们将通过神经认知、行为和神经生理学结果测量来研究洛伐他汀治疗14周对患有NF1的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确定为实现这些目标而进行更大规模研究的可行性。 公共卫生相关性：1型神经纤维瘤病(NF1)是了解认知障碍机制的一个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NF1小鼠模型中观察到的认知障碍。在这项探索性治疗拨款中，我们建议将这些发现扩展到对患有NF1的人类受试者的研究，以确定在人类接受洛伐他汀治疗后是否观察到类似的脑结构和功能变化。

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.