CincY as a Treatment for Creatine Transporter Defect

肌酸是大脑中一种重要的能量来源，它通过一种特殊的运输蛋白输送到脑组织。在美国，大约有42,000名男性受到肌酸转运体缺陷(CTD)的影响，肌酸无法进入大脑，导致严重的学习障碍、自闭症行为、反复癫痫发作和终身护理。目前还没有美国食品和药物管理局(FDA)批准的针对这类患者的治疗方法。主要合作者已经确定了一种肌酸类似物(Cincy)，即使在肌酸转运体有缺陷的情况下，它也能够穿透大脑，发挥与肌酸相同的作用。该项目的目标是将Cincy开发成治疗CTD的口服疗法。 活动概述：据估计，肌酸转运体缺陷(CTD)导致的X-连锁精神发育迟缓的比例在1%到5%之间。受影响的男性的主要临床表现是智力低下、严重的语言表达障碍和癫痫，需要终生依赖护理。肌酸转运蛋白基因敲除小鼠接受Cincy治疗，Cincy是一种重新定位的小分子，被证明能够(1)穿过血脑屏障，(2)改善小鼠的大脑新陈代谢和认知功能。Cincy已经为另一种适应症申请了非活跃的研究新药(IND)，它被证明在基因敲除小鼠模型中治疗和逆转CTD是有效的。 两组平行的脑肌酸缺乏综合征患者(GAMT和AGAT)的临床表现与CTD相似，当补充一水肌酸时，临床表现显著改善。补充一水肌酸对CTD无效，因为肌酸转运蛋白基因有缺陷，阻止肌酸越过血脑屏障。结果，在CTD患者中，当补充一水肌酸时，看不到临床改善。Cincy已被证明可以跨越血脑屏障，与大脑中的肌酸激酶相互作用，成为磷酸化的，并以与肌酸相同的方式作为能量缓冲区。TRND合作的重点是制造必要的活性药物成分(API)；完成新的化学、制造和控制(CMC)部分；以及完成所有临床前和IND使能研究。完成后，Lumos Pharma打算提交新的IND，并开始临床试验，研究Cincy在人类受试者中治疗CTD的使用。 在TRNDS接受该项目后，Lumos能够从Wellcome Trust获得额外资金，以加快团队的协作工作。TRND的科学家在疾病的动物模型中进行了药代动力学研究，以更好地了解大脑对Cincy的摄取。毒理学研究、配方开发以及化学和制造正在进行中。这些研究将使IND申请能够提交给FDA。为了支持Cincy未来的临床试验，TRND正在开发一项关于患者病程的前瞻性自然历史研究。

Creatine serves as a crucial energy source in the brain, and it is delivered to brain tissue by a specialized transport protein. Approximately 42,000 males in the U.S. are affected by creatine transporter defect (CTD), in which creatine cannot enter the brain, resulting in profound learning disabilities, autistic behavior, recurring epileptic seizures and lifelong care needs. There are no U.S. Food and Drug Administration (FDA)-approved therapies for this group of patients. The lead collaborator has identified a creatine analog (CincY) that is able to penetrate the brain and serve the same role as creatine, even when creatine transporters are defective. The goal of this project is to develop CincY into an oral therapeutic to treat CTD. Summary of activities: It is estimated that creatine transporter defect (CTD) causes between 1 and 5 percent of all X-linked mental retardation. The primary clinical manifestations of the affected males are mental retardation, severe expressive language disorder and a seizure disorder, requiring dependent care for life. Creatine transporter knockout mice were treated with CincY, a repurposed small molecule that was shown to be capable of (1) getting across the blood brain barrier and (2) improving brain metabolism and cognitive function of the mice. CincY, which has an inactive Investigational New Drug (IND) Application filed for another indication, was shown to be effective in treating and reversing CTD in the knockout mouse model. Two parallel groups of patients with brain creatine deficiency syndromes (GAMT and AGAT), which have similar clinical manifestations as CTD, show significant clinical improvement when supplemented with creatine monohydrate. Creatine monohydrate supplementation is not effective in CTD because the creatine transporter gene is defective, preventing creatine from crossing the blood-brain barrier. As a result, no clinical improvement is seen in CTD patients when supplemented with creatine monohydrate. CincY has been shown to cross the blood-brain barrier, interact with creatine kinase in the brain, become phosphorylated and act in the same way as creatine as an energy buffer. The focus of this TRND collaboration is the manufacture of necessary active pharmaceutical ingredient (API); completion of a new Chemistry, Manufacturing and Control (CMC) section; and completion of all pre-clinical and IND-enabling studies. Upon completion, Lumos Pharma intends to file a new IND and begin clinical trials to study the use of CincY to treat CTD in human subjects. After TRNDs acceptance of the project, Lumos was able to secure additional funding from the Wellcome Trust to speed the teams collaborative work. TRND scientists performed pharmacokinetic studies in animal models of the disease to better understand brain uptake of CincY. Toxicology studies, formulation development, and chemistry and manufacturing are ongoing. These studies will enable an IND application to be filed with the FDA. To support future clinical trials of CincY, TRND is developing a prospective natural history study of the disease course in patients.