Targeting System Xc- for the Treatment of Schizophrenia

描述(申请人提供)：精神分裂症是一种慢性和衰弱的疾病，影响近1%的世界人口。患者家属和照顾者的负担是巨大的，美国每年的护理成本超过600亿美元。精神分裂症过高的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。在过去的50年里，FDA批准的几乎所有抗精神病药物都只作用于多巴胺和/或5-羟色胺受体功能；然而，不幸的是，这些抗精神病药物经常与患者依从性差有关，因为疗效不佳，并出现严重的副作用，包括运动障碍和代谢/心血管副作用。这一第二阶段SBIR的总体目标是继续开发我们的新型和创新的抗精神病药物，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。具体地说，精神分裂症患者的半胱氨酸-谷氨酸交换系统(系统XC-)似乎发生了变化，我们先前在第一阶段SBIR中已经证明，针对这一机制在精神分裂症的啮齿动物模型中非常有效。目前的赠款申请旨在利用这些发现和我们的第一阶段SBIR基金，这些基金被用于发现和研究一系列针对XC-靶系统而设计的新型分子。我们的领先小分子是体外皮质培养中XC-系统的有效驱动因素，我们已经证实了在精神分裂症啮齿动物模型中的临床前疗效证明。我们建议扩大这些发现，并进一步表征我们的先导分子在IND指导的安全药理学和毒理学研究中的特征，着眼于开发一种治疗精神分裂症和潜在的其他精神疾病的新疗法。

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.