New functionalities in Orphanet for orphan drugs, R&D and marketing authorisations to better serve the rare diseases community

International audiencen.

Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. In order to help inform expert opinion, the Task Force investigated six cases of medicinal products repurposed into new rare indications and four cases of ongoing development programs. A questionnaire addressing the major steps of the repurposing approach was developed by the Task Force and sent to contact points of the organizations. In addition, interviews were conducted with the relevant organization representatives to conduct a deeper dive into the sustainability of the repurposing approach for each of the selected cases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects

Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.Primjena najkvalitetnijih dokaza kliničkih istraživanja ključna je u odabiru ispravnog liječenja pacijenata. No, način na koji će se odabrati najbolji dokazi predstavlja često poteškoću. Ovim preglednim člankom prikazujemo opasnosti navedenog odabira, kao i načine kako ih umanjiti. Relevantni izvori razmatrani su pretragom literature u kombinaciji s osobnim datotekama. Izbor liječenja uglavnom se ne bi smio temeljiti isključivo na opservacijskim ili pojedinačnim randomiziranim kliničkim studijama. Sustavni pregledi s metaanalizom svih identificiranih randomiziranih kliničkih studija procijenjenih sustavom stupnjevanja procjene, razvoja i evaluacije preporuka (engl. Grading of Recommendations Assessment, Development and Evaluation; GRADE) predstavljaju najvišu razinu dokaza. Iako su sustavni pregledi pouzdaniji od drugih vrsta dokaza, sve razine hijerarhije dokaza ugrožene su sustavnim pogreškama (engl. bias); pogreškama dizajna studije (zloupotreba surogatnih ishoda, složenih ishoda itd.) i slučajnim pogreškama (igra slučaja). Kliničke istraživačke infrastrukture mogu pomoći u pružanju većih i adekvatnije provedenih ispitivanja. Sekvencijska analiza studija može pomoći pri odlučivanju kada postoji dovoljna razina dokaza u metaanalizama. Ako se prijetnje valjanosti kliničkih istraživanja pažljivo razmatraju i minimiziraju, rezultati istraživanja bit će vrjedniji i korisniji pacientima i zdravstvenim sustavima

Evaluating the 'return on patient engagement initiatives' in medicines research and development: A literature review

Search strategy and inclusion criteria. We undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut-off of publications after July 2018. Data extraction and synthesis. Data were extracted from 91 publications, coded and thematically analysed. Main results. A total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for evaluation of benefits and costs of patient engagement. Discussion and conclusions. Currently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures

Gènes cibles de l'interleukine-4 dans les kératinocytes

Les kératinocytes sont les principales cellules de l'épiderme, la couche la plus superficielle de la peau. Dans cet organe majeur du corps humain, la communication inter-cellulaire se fait en partie, via les cytokines, parmi lesquelles l'interleukine-4 (IL-4). La stimulation des kératinocytes par l'IL-4 provoque l'activation des voies de signalisation JAK/STAT6 et MAP kinases (erk et p38) qui peuvent conduire à des modifications phénotypiques de ces cellules, ainsi qu'à la régulation de l'expression de gène cibles. Une partie de notre travail a consisté à répertorier les gènes cibles connus de l'IL-4 dans les kératinocytes ; une quinzaine de gènes ont été décrits codant pour des protéines de fonctions variées (cytokines, molécules de co-stimulation, intermédiaire de signalisation...). Nous avons également réalisé une analyse du transcriptome sur la lignée de kératinocytes humains HaCat, via la technique des biopuces ; des gènes cibles supplémentaires de l'IL-4 ont ainsi été mis en évidence (Fos B, DUSP6, HEF1...). L'interleukine-4 est présente en grande quantité au sein du tissu cutané lors de pathologies telles que la deermatite atopique. La prévalence de ce syndrome allergique ne cessant d'augmenter actuellement, il nous a semblé intéressant d'approfondir, par cette étude, la connaissance des effets de l'IL-4 sur les kératinocytes afin de mieux appréhender son rôle en situation pathologiqueCHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Régulation de l'expression et de la phosphorylation de la protéine HEF1

La protéine HEF1 est localisée principalement au niveau des adhérences focales et est impliquée dans la régulation du cytosquelette, l'adhérence et la migration cellulaires. Ses propriétés et ses interactions avec différents partenaires sont régulées par phosphorylation sur des résidus tyrosine. Elle est également phosphorylée sur des résidus sérine/thréonine en réponse à l'adhérence et au cours du cycle cellulaire. Nous avons montré que l'expression de HEF1 et régulée au niveau transcriptionnel par l'IL-4 dans les kératinocytes humains. Dans un deuxième temps, nous nous sommes intéressés à la phosphorylation sur sérine de HEF1. Nous avons identifié la sérine 369 comme étant la cible d'une kinase inhibée par l'Hesperadin, un inhibiteur d'Aurora-B. Cette phosphorylation a pour conséquence d'induire la dégradation protéasomale de HEF1. Ainsi, nous avons mis en évidence deux aspects, transcriptionnel et post-traductionnel, de la régulation de l'expression de la protéine HEF1.HEF belongs to p130Cas protein family. HEF1 is expressed in lymphocytes, fibroblasts and epithelial cells and is mainly localized at focal adhesions. This protein has been related to cytoskeleton regulation and cell adhesion and migration. Tyrosine phosphorylation influences HEF1 properties and protein-protein interactions with different partners. Cell adhesion and cell cycle progression induce also serine/threonine phosphorylation. We showed that IL-4 regulates HEF1 expression at transcriptional level in human keratinocytes. Then, we investigated HEF1 serine phosphorylation and identified serine 369 as a target for a Hesperadin inhibited kinase. Hesperadin used to be described as an inhibitor for Aurora-B kinase. Serine 369 phosphorylation induces proteasomal degradation of HEF1 protein. Here we studied the regulation of HEF1 expression at least two levels, transcriptional and post-translational.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Parcs 2050 - Connaissance et prospective des parcs automobiles (rapport intermédiaire pour la sous-action 1 des "projets de recherche sur les infrastructures et la mobilité")

This work is part of the DGITM convention aimed at supporting research on transport infrastructure and mobility. They relate specifically to vehicle fleets, mobilizing several IFSTTAR laboratories, and of interest to many actors around mobility and transport, energy and environmental issues, and public policies. The work aims at a state of the art of important or emerging issues as well as the mobilization of a national GT-PARCS working group around the problem of car fleets. Work has begun on the evolution of the composition of the vehicle fleet, the characteristics of vehicles (weight and power) and the emergence of different categories (SUVs, quads, cars without a driving licence). In relation to the 2019 version, an update of the IFSTTAR modelling of the French car fleet is underway, integrating the latest years of registration data as well as the consideration of prospective scenarios up to 2050 integrating the hypotheses of the national low carbon strategy. Finally, the GT-PARCS working group on vehicle fleets organised a seminar in June 2021 on the future of vehicle fleets and mobility, based on the major foresight exercises underway (Ademe, CGEDD, IDDRI-Université Eiffel), and integrating analyses of the evolution of emerging mobilities. This seminar brought together about 70 participants.Ces travaux s'inscrivent dans le cadre de la convention DGITM visant à soutenir des recherches sur les infrastructures et la mobilité. Ils portent spécifiquement sur les parcs automobiles, mobilisant plusieurs laboratoires de l'IFSTTAR, et intéressant de nombreux acteurs autour de problématiques mobilités et transports, énergétiques et environnementales, et les politiques publiques. Les travaux visent un état de l'art de questions importantes ou émergentes ainsi que la mobilisation d'un groupe national de travail GT-PARCS autour de la problématique des parcs automobiles. Des travaux ont débuté autour de l'évolution de la composition du parc automobile, des caractéristiques des véhicules (masses et puissances) et de l'émergence de différentes catégories (SUV, quads, voitures sans permis). Par rapport à la version 2019, une mise à jour de la modélisation IFSTTAR du parc automobile français est en cours, intégrant les dernières années de données d'immatriculations et la prise en compte de scénarios prospectifs à l'horizon 2050 intégrant les hypothèses de la stratégie nationale bas carbone. Enfin, le groupe de travail GT-PARCS sur les parcs automobile a organisé en juin 2021 un séminaire sur la prospective des parcs automobiles et des mobilités, autour des grands exercices de prospective en cours (Ademe, CGEDD, IDDRI-Université Eiffel), et intégrant les analyses d'évolution des mobilités émergentes. Ce séminaire, dont ce rapport rend essentiellement compte, a réuni près de 70 participants