Selective targeting of P13K to restore higher cognitive function in FXS

描述（由申请人提供）：对恢复智力障碍患者认知功能的治疗药物的需求尚未得到满足。脆性X综合征（FXS）是遗传性智力残疾的最常见形式。目前可用的FXS药物干预策略主要治疗行为问题。FXS研究的一个主要挑战是开发改善患者智力的治疗策略。 长期目标是更好地了解FXS认知障碍的分子机制和神经解剖学位点，并确定改善FXS患者认知功能的疾病机制靶向治疗策略。该提案的直接目标是（1）开发和测试新的临床前工具，通过在新的前额叶皮质选择性FXS小鼠模型中识别高级认知缺陷来评估FXS的认知功能，以及（2）测试磷酸肌醇-3激酶（PI 3 K）催化亚基p110？作为治疗靶点，以纠正FXS中的分子、细胞、行为，特别是高阶认知缺陷。拟议工作的理由有两方面。首先，许多研究小组鉴定改善智力能力的药物靶点的主要障碍是缺乏对小鼠高阶认知功能的合适测定，这是一种广泛使用的FXS模型系统。本提案将通过使用直接测试FXS小鼠模型中复杂认知的专门实验方法来识别和纠正高阶认知缺陷来克服这一障碍。其次，先前的工作强烈表明，PI 3 K信号传导在FXS中增加和失调，这至少部分是由翻译损失引起的。 调节PI 3 K催化亚基p110？。这证明了药理学抑制p110可以挽救FXS的分子、细胞、行为和认知表型的假设。值得注意的是，p110选择性抑制剂目前用于临床癌症试验，使p110成为FXS中特别有前途的药物靶点，可能快速应用于人类。在强有力的初步数据的支持下，该假设将通过三个目标进行检验。根据目标1，将使用病毒介导的前额叶皮层中Fmr 1的基因沉默开发一种新的FXS小鼠模型，前额叶皮层是一个对高级认知和自闭症至关重要的大脑区域。可量化的缺陷， 将鉴定这些小鼠和Fmr 1 KO小鼠中的目标导向决策。目标2和3将测试目前用于癌症患者临床试验的p110选择性抑制剂是否能挽救 分子和细胞缺陷，并改善两种FXS小鼠模型中的自闭症样行为和认知。这项研究具有重要意义和创新性，因为它将为FXS认知功能障碍的神经解剖学病因学提供独特的见解。这将是第一次， 临床评估治疗药物，以改善整个FXS表型谱，包括更高的认知。它将利用癌症研究中的“领先优势”，重新利用为癌症患者开发的p110选择性拮抗剂来治疗FXS。这种方法将克服之前FXS临床前研究的局限性并加速识别 更有效的治疗方法。

DESCRIPTION (provided by applicant): There is an unmet need for therapeutic drugs that restore cognitive function in people with intellectual disabilities. Fragile X syndrome (FXS) is th most frequent form of inherited intellectual disability. Currently available pharmacological intervention strategies for FXS primarily treat behavioral problems. A major challenge for FXS research is to develop treatment strategies that improve the intellectual capabilities of patients. The long-term goal is to better understand the molecular mechanisms and the neuroanatomical locus of cognitive impairments in FXS, and to identify disease mechanism-targeted treatment strategies that improve cognitive function in patients with FXS. The immediate objectives of this proposal are (1) to develop and test new pre-clinical tools to assess cognitive function in FXS by identifying higher-order cognitive deficiencies in a novel prefrontal cortex-selective FXS mouse model and (2) to test the phosphoinositide-3 kinase (PI3K) catalytic subunit p110¿ as a treatment target to correct molecular, cellular, behavioral, and, particularly, higher-order cognitive deficits in FXS. The rationale for the proposed work is twofold. Firstly, a major obstacl for many groups to identify drug targets improving intellectual capabilities is the lack of access to suitable assays of higher-order cognitive function in mice, a widely used model system for FXS. The present proposal will overcome this roadblock by identifying and correcting higher-order cognitive defects using a specialized experimental approach that directly tests complex cognition in FXS mouse models. Secondly, previous work strongly suggests that PI3K signaling is increased and dysregulated in FXS, which is caused, at least partially, by loss of translational regulation of the PI3K catalytic subunit p110¿. This justifies the hypothesis that pharmacological inhibition of p110¿ rescues molecular, cellular, behavioral and cognitive phenotypes of FXS. Notably, p110¿-selective inhibitors are currently used in clinical cancer trials, making p110¿ an especially promising drug target in FXS with potentially quick application in humans. Supported by strong preliminary data, the hypothesis will be tested by three aims. Under aim 1, a novel FXS mouse model will be developed using virus-mediated gene-silencing of Fmr1 in the prefrontal cortex, a brain region crucial for higher cognition and autism. A quantifiable defect in goal-directed decision-making in these and in Fmr1 KO mice will be identified. Aims 2 and 3 will test if a p110¿-selective inhibitor currently used in clinical trials with cancer patients, rescues molecular and cellular defects, and improves autistic-like behavior and cognition in the two FXS mouse models. This research is significant and innovative, because it will provide unique insight into the neuroanatomical etiology of cognitive dysfunction in FXS. It will, for the first time, pre clinically assess a therapeutic drug to improve the entire spectrum of FXS phenotypes, including higher cognition. It will take advantage of the 'head start' in cancer research by repurposing a p110¿-selective antagonist developed for use in cancer patients, to treat FXS. This approach will overcome limitations of previous pre-clinical studies in FXS and accelerate the identification of more efficient therapies.