The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

Timed coloured petri nets and their application to logistics

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In vitro model of postoncosphere development, and in vivo infection abilities of Taenia solium and Taenia saginata

Taenia solium is known to cause human cysticercosis while T. saginata does not. Comparative in vitro and in vivo studies on the oncosphere and the postoncospheral (PO) forms of T. solium and T. saginata may help to elucidate why cysticercosis can occur from one and not the other. The aim of this study was to use in vitro culture assays and in vivo models to study the differences in the development of the T. solium and T. saginata oncosphere. Furthermore, this study aimed to evaluate the expression of cytokines and metalloproteinases (MMPs) in human peripheral blood mononuclear cells (PBMCs), which were stimulated by these oncospheres and PO antigens. T. solium and T. saginata activated oncospheres (AO) were cultured in INT-407 and HCT-8 intestinal cells for 180 days. The T. solium began to die while the T. saginata grew for 180 days and developed to cysticerci in INT-407 cells. Rats were inoculated intracranially with AO and PO forms of either T. saginata or T. solium. Rats infected with T. solium AO and PO forms developed neurocysticercosis (NCC), while those infected with the T. saginata did not. Human PMBCs were stimulated with antigens of AO and PO forms of both species, and the production of cytokines and metalloproteinases (MMPs) was measured. The T. solium AO antigen stimulated a higher production of IL-4, IL-5, IL-13, IFN-γ, and IL-2 cytokines compared to T. saginata AO. In the PO form, the T. saginata PO antigen increased the production of IL-4, IL-5, IL-13, IFN-γ, IL-1β, IL-6, IL-10, TNF-α and IL-12 cytokines compared to T. solium, suggesting that this global immune response stimulated by different forms could permit survival or destruction of the parasite depending of their life-cycle stage. Regarding MMPs, T. solium AO antigen stimulated a higher production of MMP-9 compared to T. saginata AO antigen, which may be responsible for altering the permeability of intestinal cells and facilitating breakdown of the blood-brain barrier during the process of invasion of host tissue

Comportamento alimentar de ratos adultos submetidos à restrição protéica cujas mães sofreram desnutrição durante a lactação Feeding behavior of adult rats submitted to protein malnutrition whose mothers received protein restricted diets during lactation

Foi avaliado o consumo alimentar de animais adultos submetidos à restrição protéica, cujas mães receberam dieta hipoprotéica ou hipocalórica na lactação: controle (C) ração normal com 23% de proteína; restrição protéica (RP) 8% de proteína; restrição energética (RE) 23% de proteína, em quantidade restrita à ingerida pelo grupo restrição protéica. Após o desmame todos os filhotes receberam ração normal até 60 dias e nesta época foram submetidos, por 21 dias, ao seguinte tratamento: (C/C)-filhotes de mães C recebendo ração normal; (restrição protéica/controle)-filhotes de mães Controle, recebendo ração hipoprotéica; (C/RP)-filhotes de mães RP recebendo ração normal; (RP/RP)-filhotes de mães RP recebendo ração hipoprotéica; (C/RE)-filhotes de mães RE recebendo ração normal; (RP/RE)-filhotes de mães RE recebendo ração hipoprotéica. Os filhotes de mães RP consumiram menos ração até 57 dias (p<0,01), enquanto os filhotes de mães RE normalizaram a ingestão aos 37 dias. Aos 81 dias, os animais submetidos à restrição protéica consumiram menos ração (p<0,01). A dieta materna na lactação modificou o consumo alimentar e o peso corporal da prole na vida adulta, estando, possivelmente, a restrição protéica associada a uma alteração permanente no controle hipotalâmico da seleção de nutrientes da prole.<br>This study evaluated food intake of adult animals whose mothers received protein- or energy-restricted diets during lactation as follows: control (C)- 23% of protein; protein-restricted (PR) - 8% of protein; energy-restricted (ER) - 23% of protein, restricted in quantity. After weaning all pups received the control diet until 60 days, when they were separated into groups, with free access to the following diets during 21 days: (C/C)- pups of control dams fed control diet; (PR/C)-pups of control dams fed protein-restricted diet; (C/PR)- pups of protein-restricted dams fed control diet; (PR/PR)-pups of protein-restricted dams fed protein-restricted diet; (C/ER)-pups of energy-restricted dams fed control diet; (PR/ER)-pups of energy-restricted dams fed protein-restricted diet. Pups of protein-restricted dams consumed less food until day 57 (p<0.01), while pups of energy-restricted dams normalized their ingestion at 37 days. At 81 days, all malnourished animals consumed less food than the control (p<0.01). The kind of diet consumed in the lactation period changed the food intake and the body weight of the offspring in the adulthood. So, the protein restriction can possibly be associated with a permanent alteration in the hypothalamic control of nutrients selection of the offspring