Targeting System Xc- for the Treatment of Schizophrenia

描述（由申请人提供）：精神分裂症是一种慢性和使人衰弱的疾病，影响世界人口的近1%。患者家属和护理人员的负担是巨大的，美国每年的护理费用超过600亿美元。精神分裂症的过度经济压力在很大程度上是由于缺乏创新，导致治疗选择非常有限，无效和耐受性差。事实上，在过去的五十年中，FDA批准的所有抗精神病药物都仅作用于多巴胺和/或5-羟色胺受体功能;然而，不幸的是，这些抗精神病药物通常与患者依从性差有关，这是由于疗效不足和出现严重的副作用，包括运动障碍和代谢/心血管副作用。该II期SBIR的总体目标是继续开发我们的新型和创新抗精神病药物，这些药物被认为是当前护理标准的有效和更安全的替代品。具体而言，胱氨酸-谷氨酸交换（系统xc-）似乎在精神分裂症患者中发生了改变，我们先前在I期SBIR中已经表明，在啮齿动物精神分裂症模型中，靶向这种机制非常有效。目前的拨款申请旨在利用这些发现和我们的第一阶段SBIR基金，这些基金用于发现和研究一系列新的分子，这些分子被设计成靶向系统xc-。我们的先导小分子是体外皮质培养物中系统xc-的有效驱动因素，并且我们已经在啮齿动物精神分裂症模型中证实了临床前疗效证明。我们建议扩展这些发现，并在IND指导的安全药理学和毒理学研究中进一步表征我们的先导分子，着眼于开发一种治疗精神分裂症和其他潜在精神疾病的新型治疗方法。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic and debilitating disorder that impacts nearly 1% of the world's population. The burden on the families and caregivers of patients is immense, with the cost of care in the United States being greater than $60 billion annually. The exorbitant financial strain of schizophrenia arises, in large part, to a lack of innovation that has resulted in very limited, ineffective and poorly-tolerated treatment options. Virtually all of the antipsychotics approved by the FDA in the past fifty years act exclusively on dopamine and/or serotonin receptor function; however, unfortunately, these antipsychotics are routinely associated with poor patient compliance due to inadequate efficacy and the emergence of serious side effects including motor impairments and metabolic / cardiovascular side effects. The overall goal of this Phase II SBIR is to continue the development of our novel and innovative antipsychotic medications that are proposed to be an effective and safer alternative to the current standards of care. Specifically, cystine-glutamate exchange (system xc-) appears to be altered in schizophrenic patients, and we have shown previously in our Phase I SBIR that targeting this mechanism is highly effective in a rodent model of schizophrenia. This current grant application is designed to capitalize on these findings and our Phase I SBIR funds that were employed to discover and investigate a novel series of molecules engineered to target system xc-. Our lead small molecules are potent drivers of system xc- in cortical cultures in vitro and we have confirmed preclinical proof-of-efficacy in rodent models of schizophrenia. We propose to expand on these findings and further characterize our lead molecule in IND-directed safety pharmacology and toxicology studies, with an eye towards developing a novel therapeutic approach for the treatment of schizophrenia and potentially other psychiatric disorders.