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5. Accidents causés par des vecteurs adénoviraux? Etudiants: AHO Anthony (Youri) & ABDEL-SAYED Philippe --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 2/2 A. les mots-clés énoncés sont pertinents 1/2 B. Les équations corresondantes aux mots-clés manquent: on aurait aimé voir des équations du type (adenovir* OR "gene therapy" OR "viral vector" OR adenovir*) AND (incident OR accident OR "adverse effects" OR safety OR toxicity) 1/2 C. On aurait aimé voir les résultats d'une équation de recherche dans les outils Scopus et Pubmed, concernant les raisons scientifiques des accidents. Bien sur, le rapport du NIH contenait les informations essentielles à la question, mais justement, quelques tentatives de recherche d'info sur les raisons des accidents compléterait notre image mentale du problème. 1/2 D. Les références bibliographiques sont correctes, mais il manque avec quel outil elles ont été trouvées! 1/2 E. Le texte répond à la question, avec des affirmations référencées. Attention, il y a des copié-collés qui n'ont pas de guillemets, ce qui constitue un acte de plagiat! 1/2 F. Les tentatives de restitution écrite de la démarche de recherche d'information partent dans le bon sens concernant de la recherche d'information grand public, mais une volonté de recherche d'info scientifique manque. Il n'ya pas beaucoup de soins à la précision (des guillements manquent, la consigne de noter avec quel outils les références ont été trouvées manquent) 7/12 pts ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- I. SUJET Pour chaque accident causé par un vecteur adénoviral, rassemblez le plus possible d'informations:
II. ARTICLE DE REPONSE Adenovirus (Ad) vectors are the most used vectors in clinical trials in gene therapy.
"In phase I clinical trials in which a combination of adenoviral HSV-tk and chemotherapeutic agents was used to treat advanced malignant intracranial tumors, serious adverse effects have been reported, such as severe headache, relapsing seizures, and transient or persistent change of mental status."[5] In 1999, an 18-year-old Arizona man died unexpectedly in a gene therapy experiment using adenoviruses. Since then the field's safety record is coming under increasing scrutiny, and new information is coming to light about patients who may have been harmed in other clinical trials. "The Arizona patient, Jesse Gelsinger, 18, died four days after doctors at the University of Pennsylvania injected a corrective gene, encased in a deactivated adenovirus, into the hepatic artery, which leads to the liver. Leading scientists and government officials said Mr. Gelsinger was the only person known to have died as a direct result of receiving gene therapy. Other patients receiving gene therapy have died, but doctors treating them in the trials say their diseases, not the therapy, killed them. What remains unknown is how many patients experienced side effects directly related to gene therapy and what they were.[3] " The fact that an adenovirus is common to the common cold, was probably a determining factor causing scientists to overlook safety of its use in gene therapy. Scientists already know that inactivated adenovirus causes an inflammatory reaction and flu-like symptoms in patients who receive it in experiments.[3] The government's gene therapy inquiry comes amid growing concern that some researchers and companies have not been entirely forthcoming with information about the technology's harmful side effects, as well as patient deaths from causes other than gene therapy. Typically, companies experimenting with new drugs and therapies are monitored by the Food and Drug Administration, which keeps information about deaths and adverse reactions secret until a drug is approved.[3]
Preventable Mesures taken by NIH in response to patient's death in gene therapy "The possibility that the death of the research participant might be attributed to administration of the Ad vector prompted several actions on the part of the NIH. First, the NIH Office of Biotechnology Activities (OBA) alerted all principal investigators and sponsors involved with gene transfer trials using Ad vectors that a research participant had died following administration of an Ad vector. The OBA requested that investigators and sponsors involved in any Ad gene transfer clinical trial, regardless of the current status of the protocol, submit all relevant preclinical and clinical data regarding Ad vector safety, toxicity, and efficacy. At the same time, OBA also established a Recombinant DNA Advisory Committee (RAC) Working Group on Adenoviral Vector Safety and Toxicity (AdSAT) to conduct a comprehensive review and analysis of the scientific, safety, and ethical issues associated with Ad-based human gene transfer. [...] Relevant preclinical studies using the Ad vector were also considered. [...] Finally, to inform the public and provide important background information to the AdSAT Working Group, the NIH sponsored a public symposium on Ad vector safety and toxicity. This symposium brought together experts in the fields of adenovirus biology and pathophysiology, vector manufacture, hepatic physiology and coagulopathy, and cytokine and cell receptor biology." [4] The working group determined that research participant’s death most likely resulted from the high dose of Ad vector, inducing the systemic immune response. "It was noted that dose-related toxicities were observed over a very narrow dose range, leading the Working Group to consider the advisability of arithmetic rather than logarithmic dose escalations in the dose range of toxicity."[4] The RAC’s final recommendations are summarized and discussed below [4]: 1) "Standards should be developed to improve the comparability and value of experimental data collected during clinical trials. These standards would apply to the determination of vector potency (particle number, titer, dose); vector strength (transgene expression, transduction efficiency and specificity); vector quality (identity, purity, integrity, homogeneity); and vector or treatment-related toxicity (standard reporting criteria)." 2) "A centralized database should be developed for collecting and organizing gene transfer vector safety and toxicity data." 3) "The RAC will heighten attention to the issue of collection of biological data necessary to support safe product development in initial clinical trials. All vector systems should be evaluated using traditional drug development approaches, to include assessments of biodistribution; pharmacokinetics; target receptor distribution and concentration (preclinical models and human research subjects); routes and rates of administration; and characterization of therapeutic and toxic thresholds (dose escalation and response profile)." 4) "Experiments involving vector controls, whenever appropriate and meaningful, should be included in the preclinical and clinical gene transfer procedures." 5) "All research participants enrolled in gene transfer clinical trials should be monitored for several types of acute toxicities before and after vector administration. For better surveillance across all such studies, monitoring should routinely include a research participant’s immune status (both humoral and cellular), cytokine profile, and predisposing or underlying conditions that might elevate an individual’s sensitivity to a particular vector (research participant genotype, secondary and concurrent infections)." 6) "Research participants in gene transfer clinical trials should be encouraged to agree to postmortem examinations." 7) "Informed consent documents need to be improved to clarify risks and potential benefits faced by those who participate in gene transfer clinical trials." 8) "Gene transfer clinical data should be reviewed and analyzed on a regular basis in a public forum."
III. STRATEGIES DE RECHERCHE Méthode 1: Aller des sites les plus généraux aux sites plus spécifiques en suivants les liens qui semblent être les plus pertinants Exemple: Sous la page Adenovirus on a eu accès à un rapport du NIH publié dans le journal HUMAN GENE THERAPY [ref. 4]. Cette stratégie peut être utile pour la recherche d'informations sur le recensemt du nombre d'accidents, où et quand... Méthode 2: Aller sur des bases de données tels que SCOPUS, PUBMED,.... Exemple: Cette stratégie est plus utile pour la recherche d'informations sur les causes et/ou les raisons scientifiques de tels accidents. IV. DONNEES RELATIVES L'EXERCICE DE RECHERCHE Ci-dessous, une liste exaustive des tous les termes que l'on peut utiliser pour faire une recherche relative à notre sujet. (Remarque: on peut combiner plusieurs des termes ci-dessous, et on peut utiliser leur équivalent en français) gene therapy, viral vector(s), adenoviridae, adenovirus, adenoviruses, adénovirus , adenoviral, adverse effect(s), gene transfer trial(s), safety, toxicity, clinical trial(s), Jesse Gelsinger, incident
IV.2 Equations testées dans quel outil de recherche documentaire - "Adenovirus" [AND] "incident" in SCOPUS -> ref. [1] - "Thérapie génique" [AND] "mort" in Google -> ref.[2] - "adenoviral vector patient's death" in google -> ref.[3] [1] Tan, P.H., Janes, S.E., Handa, A.I., Friend, P.J. More trouble ahead; is gene therapy coming of age? Expert Opinion on Biological Therapy 8 (5), pp. 561-567, 2008. [2] http://www.caducee.net/breves/breve.asp?idb=198&mots=all. Vive polémique autour de la mort d’un adolescent traité par thérapie génique. (visité le 10.11.2008) [3] Sheryl Gay STOLBERG, A Death Puts Gene Therapy Under Increasing Scrutiny, The New York Times, Nov. 4, 1999, Section A; Page 24; Column 5 [4] Mary Ann Liebert, Inc. NIH Report Assessment of Adenoviral Vector Safety and Toxicity: Report of the National Institutes of Health Recombinant DNA Advisory Committee, HUMAN GENE THERAPY 13:3–13 (January 1, 2002) [5] Stephan A. Vorburger, |
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