Breaking Barriers:delivery of a novel therapeutic drug to promote remyelination in multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), characterized by chronic inflammation and neurodegeneration. Myelin is an insulating and protective layer that is wrapped around axons by oligodendrocytes that enables fast signal transmission between neurons. In MS demyelination is induced by an unknown trigger, resulting in the appearance of lesions. Changes in the lesion environment prevent efficient remyelination to proceed. This leads to a multitude of cognitive and physical symptoms. Fibronectin accumulates within lesions, and negatively affects remyelination. Previously, we demonstrated that a small molecule (GD1a) overcomes the remyelination-inhibiting effect of fibronectin. Treating progressive MS is difficult because of the existence of a tight layer of cells, the blood brain barrier (BBB) that separate the brain from the periphery. In this thesis we aimed to investigate modes of transporting GD1a from the periphery to the brain, while retaining its therapeutic effectiveness. GD1a-loaded and brain-targeted nanoparticles were efficiently transported across an in vitro BBB, but could not significantly improve myelin membrane formation, as GD1a likely exerts its restorative effect at the cell surface. We elucidated two interaction partners via which GD1a induces myelin membrane formation in the presence of fibronectin. As our findings also hint to potential inherent differences between an MS-BBB and their sibling-BBB in response to inflammation, inclusion of MS-derived cells is crucial to determine the success of brain delivery of remyelination therapeutics

Targeting Fibronectin to Overcome Remyelination Failure in Multiple Sclerosis:The Need for Brain- and Lesion-Targeted Drug Delivery

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood-brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS

The DECIDE project: from surveillance data to decision-support for farmers and veterinarians

Farmers, veterinarians and other animal health managers in the livestock sector are currently missing sufficient information on prevalence and burden of contagious endemic animal diseases. They need adequate tools for risk assessment and prioritization of control measures for these diseases. The DECIDE project develops data-driven decision-support tools, which present (i) robust and early signals of disease emergence and options for diagnostic confirmation; and (ii) options for controlling the disease along with their implications in terms of disease spread, economic burden and animal welfare. DECIDE focuses on respiratory and gastro-intestinal syndromes in the three most important terrestrial livestock species (pigs, poultry, cattle) and on reduced growth and mortality in two of the most important aquaculture species (salmon and trout). For each of these, we (i) identify the stakeholder needs; (ii) determine the burden of disease and costs of control measures; (iii) develop data sharing frameworks based on federated data access and meta-information sharing; (iv) build multivariate and multi-level models for creating early warning systems; and (v) rank interventions based on multiple criteria. Together, all of this forms decision-support tools to be integrated in existing farm management systems wherever possible and to be evaluated in several pilot implementations in farms across Europe. The results of DECIDE lead to improved use of surveillance data and evidence-based decisions on disease control. Improved disease control is essential for a sustainable food chain in Europe with increased animal health and welfare and that protects human health

Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?

Experimental evidence supports an intricate association between inflammation and mitochondrial dysfunction as main contributors of neurological diseases. Inflammatory mediators produced by activated microglia and infiltrated immune cells trigger intracellular signalling cascades that can alter cellular mitochondrial metabolism. Cytokines, particularly tumor necrosis factor-alpha, impede mitochondrial oxidative phosphorylation and associated ATP production and instigate mitochondrial reactive oxygen species production. This culminates in mitochondrial membrane permeabilization, altered mitochondrial dynamics and might ultimately result in cell death. When severely injured mitochondria are not appropriately removed by mitophagy they can release their contents into the cytosol and extracellular environment and thereby amplify the inflammatory process. Here we provide a comprehensive overview on how inflammatory mediators impair mitochondrial metabolism and discuss how defective mitochondria can elicit and potentiate an inflammatory response

A modeling study on the sustainability of a certification-and-monitoring program for paratuberculosis in cattle

Certification-and-monitoring programs for paratuberculosis are based on repetitive herd testing to establish a herd’s health status. The available tests have poor sensitivity. Infected but undetected herds may remain among certified “paratuberculosis-free” herds. The objective was to determine if truly free herds acquire a certified status and keep it over time when infected but undetected herds remain. The Dutch program was used as a basis to construct a mechanistic deterministic model of the evolution over 25 years of the number of herds per health status. Three health states for herds were defined: not detected as infected in the certification process to obtain a free status; not detected as infected by any of the repetitive tests for monitoring the certified free status; detected as infected. Among undetected herds, two types were defined: truly free versus undetected but infected. Transitions between states were due to the purchase of an infected animal, infection via the environment, clearance via culling or sales, detection of an infected animal, and certification. A sensitivity analysis was carried out. We showed that – for a 100% specific test only – most of the truly free herds at the beginning of the program got a certified free status and kept it over time. Most infected herds were either detected as infected or cleared. The number of certified truly free herds increased with a decrease in the animal-level prevalence or in the risk of purchasing an infected cattle, for example by restricting purchases to cattle from herds at the highest level of certification

A modeling study on the sustainability of a certification-and-monitoring program for paratuberculosis in cattle

Certification-and-monitoring programs for paratuberculosis are based on repetitive herd testing to establish a herd's health status. The available tests have poor sensitivity. Infected but undetected herds may remain among certified "paratuberculosis-free" herds. The objective was to determine if truly free herds acquire a certified status and keep it over time when infected but undetected herds remain. The Dutch program was used as a basis to construct a mechanistic deterministic model of the evolution over 25 years of the number of herds per health status. Three health states for herds were defined: not detected as infected in the certification process to obtain a free status; not detected as infected by any of the repetitive tests for monitoring the certified free status; detected as infected. Among undetected herds, two types were defined: truly free versus undetected but infected. Transitions between states were due to the purchase of an infected animal, infection via the environment, clearance via culling or sales, detection of an infected animal, and certification. A sensitivity analysis was carried out. We showed that--for a 100% specific test only--most of the truly free herds at the beginning of the program got a certified free status and kept it over time. Most infected herds were either detected as infected or cleared. The number of certified truly free herds increased with a decrease in the animal-level prevalence or in the risk of purchasing an infected cattle, for example by restricting purchases to cattle from herds at the highest level of certification

The microbiota of the grapevine holobiont: A key component of plant health

International audienceBackgroundGrapevine is a woody, perennial plant of high economic importance worldwide. Like other plants, it lives in close association with large numbers of microorganisms. Bacteria, fungi and viruses are structured in communities, and each individual can be beneficial, neutral or harmful to the plant. In this sense, microorganisms can interact with each other and regulate plant functions (including immunity) and even provide new ones. Thus, the grapevine associated with its microbial communities constitutes a supra-organism, also called a holobiont, whose functioning is linked to established plant-microorganism interactions.Aim of reviewThe overall health of the plant may be conditioned by the diversity and structure of microbial communities. Consequently, an optimal microbial composition will consist of a microbial balance allowing the plant to be healthy. Conversely, an imbalance of microbial populations could lead to (or be generated by) a decline of the plant. The microbiome is an active component of the host also responsive to biotic and abiotic changes; in that respect, a better understanding of the most important drivers of the composition of plant microbiomes is needed.Key scientific concepts of reviewThis article presents the current state of the art about the grapevine microbiota and its composition according to the plant compartments and the influencing factors. We also focus on situations of imbalance, in particular during plant disease or decline. Finally, we discuss the possible interest of microbial engineering in an agrosystem such as viticulture

A modeling study on the sustainability of a certification-and-monitoring program for paratuberculosis in cattle

Certification-and-monitoring programs for paratuberculosis are based on repetitive herd testing to establish a herd's health status. The available tests have poor sensitivity. Infected but undetected herds may remain among certified "paratuberculosis-free" herds. The objective was to determine if truly free herds acquire a certified status and keep it over time when infected but undetected herds remain. The Dutch program was used as a basis to construct a mechanistic deterministic model of the evolution over 25 years of the number of herds per health status. Three health states for herds were defined: not detected as infected in the certification process to obtain a free status; not detected as infected by any of the repetitive tests for monitoring the certified free status; detected as infected. Among undetected herds, two types were defined: truly free versus undetected but infected. Transitions between states were due to the purchase of an infected animal, infection via the environment, clearance via culling or sales, detection of an infected animal, and certification. A sensitivity analysis was carried out. We showed that--for a 100% specific test only--most of the truly free herds at the beginning of the program got a certified free status and kept it over time. Most infected herds were either detected as infected or cleared. The number of certified truly free herds increased with a decrease in the animal-level prevalence or in the risk of purchasing an infected cattle, for example by restricting purchases to cattle from herds at the highest level of certification