Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis?

Iron accumulation has been observed in mouse models and both sporadic and familial forms of Amyotrophic lateral sclerosis. Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e. chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span as compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index (BMI) were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata and motor cortex (according to MRI), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS

Les cellules leucémiques de LAL modulent-elles l'angiogenèse dans la moelle osseuse ? Rôle de l'endothéline-1 et de l'hypoxie

Increased microvessel density has been described in the bone marrow of patients with Acute Lymphoblastic Leukemia (ALL). The bone marrow is an hypoxic microenvironment, and hypoxia is an important event in triggering angiogenesis. However, the crosstalk between ALL cells and endothelial cells has not been well explored, and usual in vitro assays use cells maintained under 21% O2, which did not mimic bone marrow environment. In this study, the angiogenic activity of factors secreted by the human B-ALL Nalm-6 cell line was tested by using conditioned serum-free medium, that was applied on the human bone marrow endothelial cells HBME-1. Under 21% O2, factors secreted by Nalm-6 cells induced an angiogenic response on HBME-1 cells in vitro. This angiogenic response was not dependent on VEGF secretion but involved, at least in part, the endothelin-endothelin receptor axis. The influence of hypoxia was then studied by culturing both cell lines under 5% O2, an oxygen tension that fits the bone marrow microenvironment. Hypoxia stimulated the secretion of VEGFA by both Nalm-6 and HBME-1 cells, but the angiogenic response to leukemic conditioned medium was altered by chronic hypoxia, which affects the ability of endothelial cells to respond to endothelin-1. Thus, we concluded that leukemic secretion products did not induce angiogenesis at oxygen conditions met in vivo. This work highlights the importance of the oxygen rate in the modulation of cell interactions within the bone marrow, not yet well explored in ALL

Les cellules leucémiques de LAL modulent-elles l'angiogenèse dans la moelle osseuse ? Rôle de l'endothéline-1 et de l'hypoxie

Increased microvessel density has been described in the bone marrow of patients with Acute Lymphoblastic Leukemia (ALL). The bone marrow is an hypoxic microenvironment, and hypoxia is an important event in triggering angiogenesis. However, the crosstalk between ALL cells and endothelial cells has not been well explored, and usual in vitro assays use cells maintained under 21% O2, which did not mimic bone marrow environment. In this study, the angiogenic activity of factors secreted by the human B-ALL Nalm-6 cell line was tested by using conditioned serum-free medium, that was applied on the human bone marrow endothelial cells HBME-1. Under 21% O2, factors secreted by Nalm-6 cells induced an angiogenic response on HBME-1 cells in vitro. This angiogenic response was not dependent on VEGF secretion but involved, at least in part, the endothelin-endothelin receptor axis. The influence of hypoxia was then studied by culturing both cell lines under 5% O2, an oxygen tension that fits the bone marrow microenvironment. Hypoxia stimulated the secretion of VEGFA by both Nalm-6 and HBME-1 cells, but the angiogenic response to leukemic conditioned medium was altered by chronic hypoxia, which affects the ability of endothelial cells to respond to endothelin-1. Thus, we concluded that leukemic secretion products did not induce angiogenesis at oxygen conditions met in vivo. This work highlights the importance of the oxygen rate in the modulation of cell interactions within the bone marrow, not yet well explored in ALL

Importance of local hypoxia on endothelial phenotype for an in vitro approach to bone marrow angiogenesis

International audienceThe vasculature of bone marrow differs from that in other organs, and its characteristics should be considered when exploring the medullar angiogenesis associated with hematological malignancies. We show here that the human bone marrow sinusoidal cell line HBME-1 has a specific expression pattern of angiogenic factors and receptors, characterized by a unique VEGFR3(+), Tie2(-) signature, that resembles the in vivo pattern. Moreover, the HBME-1 cultured for up to 3 days in hypoxic conditions, similar to those found in the bone marrow, specifically downregulated expression of VEGFR1, VEGFR2 and ETAR. Thus, a model using bone marrow sinusoidal cells cultured under reduced oxygen tension may be more relevant than classical in vitro endothelial cultures for understanding the interactions between endothelial and malignant cells in the medullar microenvironment

Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.

Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen

Whole and fractionated human platelet lysate biomaterials-based biotherapy induces strong neuroprotection in experimental models of amyotrophic lateral sclerosis

International audienceAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons leading to death within 3 years and without a curative treatment. Neurotrophic growth factors (NTFs) are pivotal for cell survival. A reason for the lack of patient efficacy with single recombinant NTF brain infusion is likely to be due to the synergistic neuroprotective action of multiple NTFs on a diverse set of signaling pathways. Fractionated (protein size <50, <30, <10, <3 kDa) heat-treated human platelet lysate (HHPL) preparations were adapted for use in brain tissue with the aim of demonstrating therapeutic value in ALS models and further elucidation of the mechanisms of action. In neuronal culture all fractions induced Akt-dependent neuroprotection as well as a strong anti-apoptotic and anti-ferroptotic action. In the <3 kDa fraction anti-ferroptotic properties were shown to be GPX4 dependent highlighting a role for other platelet elements associated with NTFs. In the SOD1G86