8 research outputs found

    Drug development progress in duchenne muscular dystrophy

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    Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space

    Study on open science: The general state of the play in Open Science principles and practices at European life sciences institutes

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    Nowadays, open science is a hot topic on all levels and also is one of the priorities of the European Research Area. Components that are commonly associated with open science are open access, open data, open methodology, open source, open peer review, open science policies and citizen science. Open science may a great potential to connect and influence the practices of researchers, funding institutions and the public. In this paper, we evaluate the level of openness based on public surveys at four European life sciences institute

    Ultrasensitive detection of toxocara canis excretory-secretory antigens by a nanobody electrochemical magnetosensor assay.

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    peer reviewedHuman Toxocariasis (HT) is a zoonotic disease caused by the migration of the larval stage of the roundworm Toxocara canis in the human host. Despite of being the most cosmopolitan helminthiasis worldwide, its diagnosis is elusive. Currently, the detection of specific immunoglobulins IgG against the Toxocara Excretory-Secretory Antigens (TES), combined with clinical and epidemiological criteria is the only strategy to diagnose HT. Cross-reactivity with other parasites and the inability to distinguish between past and active infections are the main limitations of this approach. Here, we present a sensitive and specific novel strategy to detect and quantify TES, aiming to identify active cases of HT. High specificity is achieved by making use of nanobodies (Nbs), recombinant single variable domain antibodies obtained from camelids, that due to their small molecular size (15kDa) can recognize hidden epitopes not accessible to conventional antibodies. High sensitivity is attained by the design of an electrochemical magnetosensor with an amperometric readout with all components of the assay mixed in one single step. Through this strategy, 10-fold higher sensitivity than a conventional sandwich ELISA was achieved. The assay reached a limit of detection of 2 and15 pg/ml in PBST20 0.05% or serum, spiked with TES, respectively. These limits of detection are sufficient to detect clinically relevant toxocaral infections. Furthermore, our nanobodies showed no cross-reactivity with antigens from Ascaris lumbricoides or Ascaris suum. This is to our knowledge, the most sensitive method to detect and quantify TES so far, and has great potential to significantly improve diagnosis of HT. Moreover, the characteristics of our electrochemical assay are promising for the development of point of care diagnostic systems using nanobodies as a versatile and innovative alternative to antibodies. The next step will be the validation of the assay in clinical and epidemiological contexts

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    Bridging in vitro and in vivo testing: The utilisation of a novel in vitro three-dimensional model of human bone marrow for toxicity and genotoxicity testing

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    Genotoxicity testing is required for all new compounds utilising 2D assays, such as the in vitro micronucleus (MN) assay, before moving to in vivo assays such as the rodent bone marrow MN assay. Two-dimensional cell culture has traditionally been used for in vitro research. However, the in vivo setting comprises a three-dimensional (3D) environment and within the bone marrow (BM), mesenchymal and haematopoietic stem cells interact together. It has been found that even though the in vitro MN assay is intended to be predictive of the in vivo BM, glucocorticoids were found to have an increased level of micronuclei in vivo than predicted within the in vitro MN assay, therefore these have been labelled pharmacological positives. As 3D cell culture has been shown to simulate the in vivo scenario more closely, the aim of the current study was to create a reproducible model of the BM, using cell lines, which simulates the level of genotoxicity and cytotoxicity seen with the in vivo setting, for eventual use of identifying the mechanism(s) by which this change in MN induction occurs. Initially, an appropriate scaffold was identified for the primary culture of the fibroblast cell line HS-5. Once evaluated, a pre-culture of HS-5cells on the scaffold established a microenvironment suitable for later seeding of the TK6 cell line. Together with medium changes and optimised seeding a model was developed which supported an exponential phase of growth suitable for executing the MN assay in three-dimensions. Utilising this novel 3D model, TK6 cells were then dosed with known genotoxic positive (mitomycin c, etoposide and paclitaxel), negative (caffeine) and pharmacological positive (dexamethasone and prednisolone) compounds for induction of micronuclei in comparison to in vitro and historical in vivo data. The expression of 84 genes associated with metabolism was compared between 2D HS-5 vs 3D HS-5 ±TK6 to identify if this may play a role in the induction of MN. Those expressed in 3D HS-5 ±TK6 were more comparable to the in vivo BM than those HS-5 grown in 2D. In conclusion, this 3D in vitro model simulates the induction of genotoxic and cytotoxic damage of compounds, seen within the in vivo BM, with more accuracy than the conventional 2D in vitro MN assay. This research provides a more in vivo relevant setting for further in vitro investigation of the mechanism behind compound toxicity allowing a safe drug discovery pathway

    Binary-organoid particle swarm optimisation for inferring genetic networks

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    A holistic understanding of genetic interactions is crucial in the analysis of complex biological systems. However, due to the dimensionality problem (less samples and large number of genes) of microarray data, obtaining an optimal gene regulatory network is not only difficult but also computationally expensive. In this paper, a Bayesian model for the genetic interactions using the Minimum Description Length as a scoring metric is proposed. For fast optimisation of the network structure, we propose a novel Swarm Intelligence algorithm called Binary-Organoid Particle Swarm (BORG-Swarm). In BORG-Swarm we introduce the concepts of probability threshold vector and particle drift to update particle positions. Experimental studies are carried out using real-life yeast cell cycle dataset. Results indicate that existing binary swarms fail to converge and suffer from long runtimes. In constrast, BORG-Swarm's fast convergence towards the global optimum becomes apparent from results of extensive simulations
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