Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

BackgroundGene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long- term data on all PWH who receive hemophilia gene therapy.ObjectiveThe objectives of the GTR are to record the long- term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post- gene- therapy infusion.MethodsThe GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi- stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy.ResultsThe core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease.ConclusionsThe GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long- term safety and efficacy of gene therapy for hemophilia may also be addressed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/2/jth15023.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/1/jth15023_am.pd

World Federation of Hemophilia Gene Therapy Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/2/hae14015_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/1/hae14015.pd

Genetic analysis of the effect of «Nramp 1» on the host and pathogen genomes in the context of chronic «Salmonella» infection

In humans, Salmonella infections cause two major clinical diseases: salmonellosis and typhoid fever. Silent carriage of the bacteria is frequent and contributes to disease dissemination. Using a genomic approach, we have reported the identification of ten loci (Ses1-Ses10) affecting Salmonella persistence in mice. A major locus, Ses1, was validated using a congenic approach. Nramp1 remains a strong candidate gene for Ses1 although we did not detect a significant interaction between Ses1 and Nramp1-/-. We also present the creation of new double congenic strains (Ses1/Ses4 and Ses1/Ses5) that will be used to validate the inheritance model of Salmonella clearance in females. Furthermore, the influence of Nramp1 on the transcriptome of Salmonella was investigated and diverse virulence mechanisms were shown to be involved. Notably, differential phoP expression, and the resulting differential expression of PhoP-regulated genes, was observed in the presence of Nramp1. Our results confirm the importance of host-pathogen interactions in determining the outcome of infection.Les infections à salmonelles regroupent différentes maladies dont la salmonellose et la fièvre typhoïde. Le portage asymptomatique des salmonelles est fréquent et contribue à la dissémination de la maladie. En utilisant une approche de criblage génomique par locus, nous avons identifié dix loci (Ses1-Ses10) affectant la persistance de Salmonella chez la souris. Un locus majeur, Ses1, a été validé en utilisant des souris congéniques. Nramp1 demeure un gène candidat de choix pour Ses1 quoiqu’un test d’interaction Ses1/Nramp1-/- se soit avéré non significatif. Le modèle proposé de portage de Salmonella incluant des interactions entre les loci Ses1/Ses4 et Ses1/Ses5 sera exploré par la création de nouvelles lignées congéniques combinatoires qui ont été créées durant la préparation de cette thèse. L'influence de Nramp1 sur le transcriptome de Salmonella a été étudiée au niveau des mécanismes bactériens de virulence. En particulier, nous avons observé une expression différentielle de phoP, et par conséquent l’expression différentielle de gène dont l’expression est contrôlée par PhoP, en présence de Nramp1. Nos résultats confirment l'importance des interactions hôte-pathogène dans l’issue de l'infection à salmonelles