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衰弱性疾病，影响着世界上近1%的人口。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。精神分裂症过高的财政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、无效和难以耐受。在过去的50年里，几乎所有被FDA批准的抗精神病药物都只作用于多巴胺和/或血清素受体的功能；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，因为它们的疗效不足，并且出现了严重的副作用，包括运动障碍和代谢/心血管副作用。二期SBIR的总体目标是继续开发新的创新抗精神病药物，这些药物被认为是当前治疗标准的有效和更安全的替代方案。具体来说，半胱氨酸-谷氨酸交换（系统xc-）似乎在精神分裂症患者中发生了改变，我们已经在之前的I期SBIR中表明，针对这种机制在精神分裂症啮齿动物模型中非常有效。目前的拨款申请旨在利用这些发现和我们的I期SBIR资金，用于发现和研究一系列针对系统xc-的新型分子。我们的先导小分子在体外皮层培养物中是系统xc-的有效驱动因素，我们已经在精神分裂症啮齿动物模型中证实了临床前疗效。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.