CincY as a Treatment for Creatine Transporter Defect

肌酸是大脑中至关重要的能量来源，它通过一种专门的运输蛋白质输送到脑组织。在美国，大约有42，000名男性受到肌酸转运蛋白缺陷（CTD）的影响，其中肌酸无法进入大脑，导致严重的学习障碍，自闭症行为，复发性癫痫发作和终身护理需求。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。首席合作者已经确定了一种肌酸类似物（CRAY），即使肌酸转运蛋白有缺陷，它也能够穿透大脑并发挥与肌酸相同的作用。该项目的目标是将BACHYY开发成治疗CTD的口服治疗剂。 活动摘要：据估计，肌酸转运蛋白缺陷（CTD）导致所有X连锁精神发育迟滞的1%至5%。受影响的男性的主要临床表现是智力迟钝、严重的表达性语言障碍和癫痫发作障碍，需要终生依赖性护理。肌酸转运蛋白基因敲除小鼠接受了NAPY治疗，NAPY是一种重新设计的小分子，被证明能够（1）穿过血脑屏障和（2）改善小鼠的脑代谢和认知功能。在另一种适应症中提交了非活性研究性新药（IND）申请的BACHYY被证明在基因敲除小鼠模型中有效治疗和逆转CTD。 两个平行组的患者脑肌酸缺乏综合征（GAMT和AGAT），具有类似的临床表现CTD，显示出显着的临床改善时，补充肌酸一水合物。肌酸一水合物补充剂对CTD无效，因为肌酸转运蛋白基因有缺陷，阻止肌酸穿过血脑屏障。因此，当补充肌酸一水合物时，在CTD患者中未观察到临床改善。已经证明，肌酸激酶可以穿过血脑屏障，与大脑中的肌酸激酶相互作用，磷酸化，并以与肌酸相同的方式作为能量缓冲。此次TRND合作的重点是生产必要的活性药物成分（API）;完成新的化学、生产和控制（CMC）部分;以及完成所有临床前和IND使能研究。完成后，Lumos Pharma打算提交一份新的IND，并开始临床试验，以研究在人类受试者中使用BELLY治疗CTD。 在TRND接受该项目后，Lumos能够从威康信托基金获得额外的资金，以加快团队的协作工作。TRND的科学家们在该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CYP 1AY的摄取。毒理学研究、制剂开发、化学和生产正在进行中。这些研究将使IND申请能够提交给FDA。为了支持未来的临床试验，TRND正在开发一项前瞻性的自然史研究，研究患者的疾病过程。

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.