LUM-001 as a Treatment for Creatine Transporter Deficiency

据估计，肌酸转运蛋白缺乏(CTD)导致了所有X-连锁智力低下的1%到5%。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了Lum-001的治疗，Lum-001是一种重新定位的小分子，被证明能够(1)穿过血脑屏障，(2)改善小鼠的大脑代谢和认知功能。LUM-001已经为另一种适应症申请了非活跃的研究新药(IND)，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。因此，在CTD患者中，当补充一水肌酸时，并没有测量到临床改善。Lum-001已被证明可以穿过血脑屏障，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来源。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。 在TRNDS接受该项目后，Lumos能够从Wellcome Trust和风险投资公司获得额外资金，以加快团队的协作工作。TRND的科学家在这种疾病的动物模型中进行了药代动力学/分布研究，以更好地了解大脑对Lum-001的摄取。完成了毒理学研究、配方开发以及化学和制造，以支持IND在健康志愿者中的应用和启动一期临床安全性研究。为了支持未来的Lum-001临床试验，TRND正在与Lumos合作，对多个地点的患者的病程进行预期的自然历史研究，包括2017年启动的NIH临床中心，该中心目前正在进行中。

It is estimated that creatine transporter deficiency (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 LUM-001, 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. LUM-001, 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 has been measured in CTD patients when supplemented with creatine monohydrate. LUM-001 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 source. 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. After TRNDs acceptance of the project, Lumos was able to secure additional funding from the Wellcome Trust and venture capital firms to speed the teams collaborative work. TRND scientists performed pharmacokinetic/distribution studies in animal models of the disease to better understand brain uptake of LUM-001. Toxicology studies, formulation development, and chemistry and manufacturing were completed to support an IND application and initiation of a Phase 1 clinical safety study in healthy volunteers. To support future clinical trials of LUM-001, TRND is collaborating with Lumos on a prospective natural history study of the disease course in patients at multiple sites, including the NIH Clinical Center that was initiated in 2017 and is currently on-going.