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.

Start Date05 Jun 2024

Sponsor / Collaborator

Pelage Pharmaceuticals, Inc.

100 Clinical Results associated with MPC2 x MPC1

100 Translational Medicine associated with MPC2 x MPC1

0 Patents (Medical) associated with MPC2 x MPC1

Literatures (Medical) associated with MPC2 x MPC1

01 Oct 2024·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

Author: 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.

01 Dec 2023·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

Author: 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.

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

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

Review

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

Objective: To analyze the clinical and genetic features of patients with mitochondrial pyruvate carrier deficiency (MPYCD). Methods: This was a case series research. The clinical data, genetic characteristics, and glutamine treatment efficacy of 3 patients diagnosed with MPYCD at the Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, Guizhou Provincial People's Hospital, from August 2019 to June 2023 were retrospectively collected. A literature search with "MPC1 gene" "MPC2 gene and" "mitochondrial pyruvate carrier deficiency" as keywords was conducted at the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI) and PubMed (up to June 2023). Clinical and genetic characteristics of patients with MPYCD were summarized. Results: Case 1 was a 3 years and 11 months old boy, while case 2 was a 4 years and 10 months old boy and case 3 was an 8 years and 9 months old girl. Case 2 and case 3 were siblings from one consanguineous family. All 3 patients presented with general developmental delay, growth failure and elevated serum lactate. Cranial magnetic resonance imaging (MRI) showed subtle bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus in case 1, but normal in case 2 and 3. Trio-WES revealed case 1 harboring compound heterozygous missense variants c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1 gene, while case 2 and 3 revealed a homozygous variant c.290G>A (p.Arg97Gln) in the same gene. All 3 cases were diagnosecl as MPYCD. Clinical symptoms including motor ability, cognition and activity endurance were improved in these 3 patients after taking glutamine for 2 years. A total of 5 articles published in English were reviewed, and no Chinese literature was found. Including these 3 cases, 15 cases were enrolled for analysis. Eleven patients carried MPC1 gene variants and 4 cases carried MPC2 gene variants. Except for 3 cases died during prenatal period, 9 of 12 enrolled born cases were onset before 6 months old. The most common clinical symptoms were mental and motor general developmental delay, microcephaly, growth failure and hypotonia. All patients had elevated blood lactate and pyruvate, but the ratio of lactate/pyruvate was normal. Seven patients performed cranial MRI, 3 exhibited non-specific changes, 2 showed bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus, and 3 were normal. A total of 5 MPC1 gene missense variants and 2 MPC2 gene variants were identified in 15 cases. Conclusions: Onset age of patients with MPYCD is usually within 6 months. The main clinical characteristics are developmental delay, microcephaly and growth failure, accompanied by increased serum lactate and pyruvate. Glutamine supplement could lead to clinical improvements.

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