A RANDOMIZED PLACEBO-CONTROLLED STUDY OF LOVASTATIN (TM) IN CHILDREN WITH

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 儿童期NF 1最常见的神经系统并发症是认知缺陷，对此没有有效的特异性药物治疗。研究表明，LovastinTM可以逆转Nf 1 +/-小鼠中观察到的生化、电生理和认知缺陷，使其达到与野生型对照小鼠相当的水平。 用Lovastatin TM处理的Nf 1 +/-小鼠表现出空间学习和记忆任务（通过Morris水迷宫测量）、注意力和前脉冲抑制的改善。 假设这些任务反映了NF 1儿童的认知缺陷。 莫里斯水迷宫涉及学习和记忆机制，这依赖于海马功能。 虽然在NF 1儿童中已经报道了视觉空间缺陷（例如，Skirmisher，Billingsley，Slopes &摩尔，2003），但是没有研究报道该队列中的视觉空间学习能力。 以抑制ras为目标的Lovastatin TM是NF 1和认知缺陷儿童的潜在治疗干预的合理选择。 临床试验表明，Lovastatin TM治疗成人和儿童heFH有效且安全。 来自最近完成的I期试验的结果表明Lovastatin TM用于患有NF 1的儿童（10-17岁）是安全的（Acosta等人，2007年）。 目前，没有研究检查Lovastatin TM对NF 1患者认知功能的影响。本研究将确定Lovastatin TM治疗NF 1儿童认知缺陷的疗效。我们将开展一项多中心、随机、双盲、II期临床试验，包括两个治疗组（Lovastatin TM/安慰剂），为期16周。根据NF 1小鼠模型的预测，预计视觉空间学习任务和/或注意力任务受损的NF 1儿童将受益于Lovastatin TM。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most common neurological complication of NF1 in childhood is cognitive deficits for which there are not effective specific pharmacological treatments. Studies indicate that LovastatinTM can reverse the biochemical, electrophysiological and cognitive deficits observe in Nf1 +/- mice to levels comparable to wild-type control mice. Nf1+/- mice treated with LovastatinTM demonstrated improved performance on tasks of spatial learning and memory (as measured by the Morris Water maze), attention, and pre-pulse inhibition. These tasks are hypothesized to reflect the cognitive deficits observed in children with NF1. The Morris Water Maze involves mechanisms of learning and memory, which relies on hippocampal functioning. While visual-spatial deficits have been reported in children with NF1 (e.g. Skirmisher, Billingsley, Slopes & Moore, 2003), no studies have reported on the visual spatial learning abilities in this cohort. LovastatinTM, which targets the inhibition of ras, is a logical choice as a potential therapeutic intervention for children with NF1 and cognitive deficits. Clinical trials indicate that LovastatinTM is effective and safe to treat heFH in adults and children. Results from a recently completed Phase I trial indicate that LovastatinTM is safe to be used in children (10-17 years) with NF1 (Acosta et al., 2007). Currently, no studies have examined the effect of LovastatinTM on cognitive functioning in individuals with NF1. This study will determine the efficacy of LovastatinTM as a treatment for the cognitive defects observed in children with NF1. We will conduct a multi-centre randomized, double-blind, Phase II trial with two treatment arms (LovastatinTM/placebo) for 16 weeks. Based on predictions from the NF1 murine mouse model, it is expected that children with NF1, who are impaired on a visual spatial learning task and/or an attention task, will benefit from LovastatinTM.