Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide:A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study

Introduction This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on blood/urine biomarkers and cerebral activity. Methods Participants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose. Results The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG). Conclusion NX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing

Low charge noise quantum dots with industrial CMOS manufacturing

Silicon spin qubits are among the most promising candidates for large scale quantum computers, due to their excellent coherence and compatibility with CMOS technology for upscaling. Advanced industrial CMOS process flows allow wafer-scale uniformity and high device yield, but off the shelf transistor processes cannot be directly transferred to qubit structures due to the different designs and operation conditions. To therefore leverage the know-how of the micro-electronics industry, we customize a 300mm wafer fabrication line for silicon MOS qubit integration. With careful optimization and engineering of the MOS gate stack, we report stable and uniform quantum dot operation at the Si/SiOx interface at milli-Kelvin temperature. We extract the charge noise in different devices and under various operation conditions, demonstrating a record-low average noise level of 0.61 ${\mu}$eV/${\sqrt{Hz}}$ at 1 Hz and even below 0.1 ${\mu}$eV/${\sqrt{Hz}}$ for some devices and operating conditions. By statistical analysis of the charge noise with different operation and device parameters, we show that the noise source can indeed be well described by a two-level fluctuator model. This reproducible low noise level, in combination with uniform operation of our quantum dots, marks CMOS manufactured MOS spin qubits as a mature and highly scalable platform for high fidelity qubits.Comment: 22 pages, 13 figure

NX210c Peptide Promotes Glutamatergic Receptor-Mediated Synaptic Transmission and Signaling in the Mouse Central Nervous System

NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions

Abstract CT113: A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut

International audienceAsparaginases are a cornerstone in the treatment of ALL, but their utility is limited by toxicities including hypersensitivity. ERY001 improves pharmacokinetics and tolerability, while maintaining circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. This phase III study enrolled pts with primary relapsed/refractory Ph- ALL. The co-primary endpoints were the duration of ASPA activity equal or greater than 100IU/L and the incidence of ASPA hypersensitivity during induction. Patients, aged 1-55 years, without prior ASPA hypersensitivity were randomized to ERY001 (150 IU/kg) or L-ASP(10.000IU/m2) in combination with COOPRALL. The patients with prior ASPA hypersensitivity received ERY001. ERY001 significantly reduced the incidence of ASPA hypersensitivity (0% vs 43%; p100IU/l significantly longer than L-ASP (20.5±5.2 vs 9.2±7.5 days; p\textless0.001). CR and clotting parameters were also significantly improved in the ERY001 arm. Other adverse events were generally similar in. One-year OS was 77% in the ERY001 arm vs 68% in L-ASP arm. ASPA activity was not reduced in hypersensitive patients. These highly encouraging results show that ERY001 is a suitable option for patients with relapsed ALL maintaining ASPA efficacy with improved tolerability. Citation Format: Yves Bertrand, Andre Baruchel, Xavier Thomas, Nicolas Blin, Emmanuelle Tavernier, Yves Perel, Norbert Vey, Virginie Gandemer, Iman ElHariry, Yann Godfrin. A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT113. doi:10.1158/1538-7445.AM2015-CT11

Peptide formulation and development of a novel delivery system for the treatment of neurological pathologie

International audienc

Biodegradable hydrogel for sustained release of therapeutic peptide

International audienc

Biodegradable hydrogel for sustained release of therapeutic peptide

International audienc

Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Buffalo/Mna rats spontaneously develop a focal segmental glomerulosclerosis with a histological pattern similar to the human disease. In this study, we investigated the potential of recurrence of the disease by transplantation of normal kidneys into Buffalo/Mna recipients. Kidneys from healthy LEW.1W rats were grafted into proteinuric 6-month-old Buffalo/Mna rats without or with specific tolerance induction following donor-specific transfusion (DST) aimed at controlling host anti-donor immune responses. The inverse combination was carried out to determine whether a proteinuric Buffalo/Mna kidney can recover its permselectivity in a normal environment. As a control, LEW.1W kidneys were grafted into Wistar Furth recipients. After transplantation without DST, recurrence of proteinuria in LEW.1W kidneys appeared at approximately 10 days, possibly associated with rejection of the graft. In the same combination with DST, proteinuria occurred after 20 days, and the attendant glomerular damage suggested that the initial kidney disease had recurred. Transplanted control animals remained free of proteinuria. In the opposite combination, the proteinuria and the lesions of Buffalo/Mna kidneys regressed after transplantation into healthy LEW.1W rats. The recurrence of proteinuria after transplantation in Buffalo/Mna and the remission of lesions in Buffalo/Mna kidneys transplanted into normal hosts suggests that Buffalo/Mna rats express circulating albuminuric factors, which may be relevant to the relapse of idiopathic nephrotic syndrome in humans