Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study.

Introduction: Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells.

NX210c drug candidate peptide strengthens mouse and human blood-brain barriers.

Background: Alterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.

Evaluation of lipophosphoramidates-based amphiphilic compounds on the formation of biofilms of marine bacteria.

The bacteriostatic and/or bactericidal properties of few phosphoramide-based amphiphilic compounds on human pathogenic bacteria were previously reported. In this study, the potential of two cationic ( and ) and two zwitterionic ( and ) amphiphiles as inhibitors of marine bacterial growth and biofilm formation were investigated. Results showed that the four compounds have little impact on the growth of a panel of 18 selected marine bacteria at a concentration of 200 µM, and up to 700 µM for some bacterial strains.

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.

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.

Trophic transfer of copper decreases the condition index in Crassostrea gigas spat in concomitance with a change in the microalgal fatty acid profile and enhanced oyster energy demand.

Due to new usages and sources, copper (Cu) concentrations are increasing in the Arcachon Basin, an important shellfish production area in France. In the present paper, the trophic transfer of Cu was studied between a microalga, Tetraselmis suecica, and Crassostrea gigas (Pacific oyster) spat. An experimental approach was developed to assess Cu exposure, transfer and toxicity on both phytoplankton and spat.

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e.

SCO-spondin-derived Peptide Protects Neurons from Glutamate-induced Excitotoxicity.

Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis, that strongly contributes to neuronal development. The SCO becomes atrophic in adults, halting SCO-spondin production and its neuroprotective functions. Using rat and human neuronal cultures, we evaluated the neuroprotective effect of an innovative peptide derived from SCO-spondin against glutamate excitotoxicity.

subsp. subsp. nov., pathogenic to the edible cockles in France, and establishment of subsp. subsp. nov. and subsp. subsp. nov.

Cockle mortality events have been reported in northern France since 2012. In the present study, we describe and investigate the implication of a potential bacterial causative agent in cockle mortality. Bacteria isolated from five different cockle mortality events were characterized and studied.

Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6.

Erymet is a new therapy resulting from the encapsulation of a methionine gamma-lyase (MGL; EC number 4.4.1.

Drug-loaded erythrocytes: on the road toward marketing approval.

Erythrocyte drug encapsulation is one of the most promising therapeutic alternative approaches for the administration of toxic or rapidly cleared drugs. Drug-loaded erythrocytes can operate through one of the three main mechanisms of action: extension of circulation half-life (bioreactor), slow drug release, or specific organ targeting. Although the clinical development of erythrocyte carriers is confronted with regulatory and development process challenges, industrial development is expanding.

Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma.

Objectives: Asparaginase encapsulated in erythrocytes (ERY-ASP) is a potentially effective drug in patients with pancreatic adenocarcinoma (PAC) with null/low asparagine synthetase (ASNS) expression. Our aims were to assess ASNS expression in PAC from a large cohort and its prognostic and/or predictive value and to conduct a phase I trial with ERY-ASP in patients with metastatic PAC.

Methods: Asparagine synthetase expression was evaluated using immunohistochemistry in resected PAC (471 patients) and in pairs of primary tumor and metastases (55 patients).

A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study.

Purpose: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Findings: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days.

Innovative approach in Pompe disease therapy: Induction of immune tolerance by antigen-encapsulated red blood cells.

Pompe disease is a glycogen storage disease caused by acid α-glucosidase enzyme deficiency. Currently, the unique treatment is lifelong enzyme replacement therapy ERT with frequent intravenous administration of the recombinant analog alglucosidase-α (AGA), which ultimately generates a sustained humoral response resulting in treatment discontinuation. Our aim is to use the tolerogenic properties of antigen-encapsulated red blood cells (RBCs) to abolish the humoral response against AGA and to restore tolerance to replacement therapy.

Erythrocytes encapsulated with phenylalanine hydroxylase exhibit improved pharmacokinetics and lowered plasma phenylalanine levels in normal mice.

Enzyme replacement therapy is often hampered by the rapid clearance and degradation of the administered enzyme, limiting its efficacy and requiring frequent dosing. Encapsulation of therapeutic molecules into red blood cells (RBCs) is a clinically proven approach to improve the pharmacokinetics and efficacy of biologics and small molecule drugs. Here we evaluated the ability of RBCs encapsulated with phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe) from the blood and confer sustained enzymatic activity in the circulation.

Hypoxia/reoxygenation stress increases markers of vaso-occlusive crisis in sickle SAD mice.

In sickle cell disease, the factors involved in vasoocclusive crisis (VOC) include the sickling of red blood cells (RBC), abnormal blood rheology, inflammation, vascular adhesion, oxidative stress, coagulation, and vascular tone modulation. The aim of this study was to further characterize the molecular response of some factors involved in VOC by inducing a hypoxia/reoxygenation stress in sickle SAD mice. Results show that a hypoxia/reoxygenation stress in SAD mice can induce: (i) a decrease in reticulocytes count, and mean corpuscular volume along with an increase in lactate dehydrogenase (p = 0.

Red blood cells as innovative antigen carrier to induce specific immune tolerance.

The route of administration, the dose of antigen as well as the type of antigen-presenting cells (APCs) targeted are important factors to induce immune tolerance. Despite encouraging results obtained in animal models, intravenous injection of soluble antigen is unsuccessful in human clinical trials on autoimmune disease due to inefficient antigen delivery. To improve antigen delivery, we used mouse red blood cells (RBCs) as antigen vehicles to specifically target APCs which are responsible for removal of senescent RBCs after phagocytosis.

Effect of inositol hexaphosphate-loaded red blood cells (RBCs) on the rheology of sickle RBCs.

Background: The recent in vitro demonstration that inositol hexaphosphate-loaded red blood cells (IHP-RBCs) may reduce the risks of sickling of sickle RBCs (SS RBCs) exposed to hypoxia make these modified RBCs potentially useful in transfused sickle cell anemia (SCA) patients.

Study Design And Methods: Hemorheologic properties of IHP-RBCs, normal RBCs (AA RBCs), SS RBCs, SS RBCs plus AA RBCs, and SS RBCs plus IHP-RBCs were compared under normoxia and/or after hypoxic challenges.

Results: Although IHP-RBCs have reduced deformability compared with SS RBCs or AA RBCs, IHP-RBCs exhibited lower aggregability than AA RBCs and SS RBCs and, when mixed with SS RBCs, the aggregation level was below the one of SS RBCs alone or SS RBCs plus AA RBCs.

Tumor growth control using red blood cells as the antigen delivery system and poly(I:C).

The goal of most current vaccines in tumor immunology is to induce an efficient immune response against the tumor cells. The use of red blood cells (RBCs) for the delivery of tumor-associated antigen to antigen-presenting cells is an innovative approach for cancer immunotherapy. The induction of antigen-specific immune responses after administration of antigen-loaded RBCs has been demonstrated previously in mice.

Pancreatic tumor sensitivity to plasma L-asparagine starvation.

Objectives: In this study, our aim was to test whether asparagine synthetase (ASNS) deficiency in pancreatic malignant cells can lead to sensitivity to asparagine starvation. We also investigated, in tumor-bearing mice, the efficacy of L-asparaginase entrapped in red blood cells (RBCs), a safe formulation, to induce asparagine depletion.

Methods: First, ASNS expression was evaluated by immunohistochemistry in sporadic pancreatic ductal adenocarcinoma.

Efficacy of homologous inositol hexaphosphate-loaded red blood cells in sickle transgenic mice.

Patients with sickle cell disease (SCD) can present several severe symptoms during their lifetime, including painful events due to vascular occlusion (VOC). Even though multiple factors are involved in VOC, hypoxia is the most important triggering factor. Inositol hexaphosphate (IHP) reduces the oxygen-haemoglobin affinity thus improving the oxygen release in the blood stream and in the tissues.

International seminar on the red blood cells as vehicles for drugs.

The first human transfusion was performed by the pioneer Dr Jean-Baptiste Denis in France in 1667 and now, three centuries later, around 50 millions blood units are transfused every year, saving millions of lives. Today, there is a new application for red blood cells (RBCs) in cellular therapy: the effective use of erythrocytes as vehicles for chemical or biological drugs. Using this approach, the therapeutic index of RBC-entrapped molecules can be significantly improved with increased efficacy and reduced side effects.

l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial.

l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E.