A Randomized, Multicenter, Double-blind, Vehicle-controlled, Phase 2a Study to Assess the Safety, Pharmacokinetics, and Efficacy of PP405 in Adults With Androgenetic Alopecia

The study is designed to validate safety results from the Phase 1 PP405-001 trial while also characterizing longer term safety and PK following 28 days of administration.

开始日期2024-06-05

申办/合作机构

Pelage Pharmaceuticals, Inc.

100 项与 MPC2 x MPC1 相关的临床结果

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100 项与 MPC2 x MPC1 相关的转化医学

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0 项与 MPC2 x MPC1 相关的专利（医药）

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项与 MPC2 x MPC1 相关的文献（医药）

2024-10-01·Neurobiology of Disease

Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease

Article

作者: Millet, Philippe ; Martinou, Jean-Claude ; Ceyzériat, Kelly ; Montessuit, Sylvie ; Nicolaides, Alekos ; Petrelli, Francesco ; Badina, Aurélien M ; Tournier, Benjamin B ; Savioz, Armand

Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aβ and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aβ and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aβ and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.

2023-12-01·Biochimica et Biophysica Acta (BBA) - General Subjects

Screening for new inhibitors of the human Mitochondrial Pyruvate Carrier and their effects on hepatic glucose production and diabetes

Article

作者: Martinou, Jean-Claude ; Li, Lingzi ; Jiménez-Sánchez, Cecilia ; Maechler, Pierre ; Herzig, Sébastien

BACKGROUNDThe mitochondrial pyruvate carrier (MPC) is a protein complex composed of two subunits, MPC1 and MPC2. This carrier is at the interface between glycolysis and mitochondrial metabolism and plays an essential role in hepatic glucose production.METHODSHere we describe an in vitro screen for small molecule inhibitors of the MPC using a strain of Lactococcus lactis that has been engineered to co-express the two subunits of the human MPC and is able to import exogenous 14C-pyruvate. We then tested the top candidates for potential antidiabetic effects through the repression of gluconeogenesis.RESULTSBy screening the Prestwick compound library of 1'200 drugs approved by the Food and Drug Administration for inhibitors of pyruvate uptake, twelve hit molecules were identified. In a secondary screen, the most potent inhibitors were found to inhibit pyruvate-driven oxygen consumption in mouse C2C12 muscle cells. Assessment of gluconeogenesis showed that Zaprinast, as well as the established MPC inhibitor UK5099, inhibited in vitro and in vivo hepatic glucose production. However, when tested acutely in mice without the administration of gluconeogenic substrates, MPC inhibitors raised blood glucose levels, pointing to liver-independent effects. Furthermore, chronic treatment with Zaprinast failed to correct hyperglycemia in both lean and obese diabetic mouse models.CONCLUSIONSNew MPC inhibitors have been identified, showing inhibitory effects on hepatic glucose production.GENERAL SIGNIFICANCEFor potential antidiabetic applications, MPC inhibitors should target the liver without undesired inhibition of mitochondrial pyruvate metabolism in the skeletal muscles or pancreatic beta-cells in order to avoid dual effects on glycemia.

2023-11-02·Zhonghua er ke za zhi = Chinese journal of pediatrics

[Mitochondrial pyruvate carrier deficiency: 3 cases report and literature review].

Review

作者: Xu, C L ; Fu, X L ; Jiang, H F ; Fang, F ; Liu, Z M ; Zhao, P Q

目的： 总结线粒体丙酮酸载体缺陷症（MPYCD）的临床和遗传特征。 方法： 病例系列研究。总结2019年8月至2023年6月首都医科大学附属北京儿童医院神经内科和贵州省人民医院儿科诊治的3例MPYCD患儿的临床资料、遗传学特征及谷氨酰胺治疗效果。分别以“MPC1”“MPC2”“线粒体丙酮酸载体缺陷症”“mitochondrial pyruvate carrier deficiency”为关键词对万方数据库、中国知网及PubMed数据库建库至2023年6月的文献进行检索，总结MPYCD的临床和遗传学特征。 结果： 例1，男，3岁11月龄；例2（男，4岁10月龄）和例3（女，8岁9月龄）为同胞姐弟。3例患儿均表现为智力及运动发育落后、生长受限和血乳酸升高。例1头颅磁共振成像（MRI）示双侧对称性基底节区、丘脑T2稍长信号，例2和例3头颅MRI正常。基因检测提示MPC1基因变异，例1为c.208G>A（p.Ala70Thr）和c.290G>A（p.Arg97Gln）复合杂合变异。例2和例3均为c.290G>A（p.Arg97Gln）纯合变异。3例均诊断为MPYCD。谷氨酰胺治疗2年，3例患儿的运动、认知和活动耐力有不同程度改善。检索符合条件的中文文献0篇，英文文献5篇，包括本组3例共有15例MPYCD患者（11例MPC1基因变异、4例MPC2基因变异）。除外3例胎儿期死亡，总结12例患儿的临床特点，9例在6月龄内起病。常见的临床表现是智力和运动全面落后（12例）、小头畸形（7例）、生长受限（6例）和肌张力减低（6例）。所有患儿均有血乳酸和丙酮酸升高，但乳酸/丙酮酸正常。7例患儿有头颅MRI资料，其中3例有脑萎缩、脑室扩张等改变，2例有双侧对称性基底节、丘脑异常信号，3例正常。共发现5个MPC1基因变异位点和2个MPC2基因变异位点，包括6个错义变异，1个核苷酸改变导致起始密码子改变。 结论： MPYCD患者多在6月龄内起病，主要表现为全面发育落后、小头畸形和生长受限，伴高乳酸和高丙酮酸血症，谷氨酰胺可在一定程度上改善症状。.