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Your search keyword '"Visigalli, I."' showing total 2 results
Start Over Author "Visigalli, I." Journal science translational medicine
2 results on '"Visigalli, I."'

1. Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates

Author

Mauro Biffi, Daniela Cesana, Federica Moalli, Tongyao Liu, Matteo Iannacone, Douglas Drager, Patrizia Cristofori, Sara Bartolaccini, Fabio Russo, Andrea Raimondi, Alessio Cantore, Ilaria Visigalli, Robert T. Peters, Eugenio Montini, Andrea Calabria, Michela Milani, Susannah Patarroyo-White, Andrea Annoni, Eduard Ayuso, Luigi Naldini, San Raffaele Telethon Institute for Gene Therapy [Milan, Italy] (SR-Tiget), Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, IRCCS Ospedale San Raffaele [Milan, Italy], Bioverativ [Waltham, MA, USA], GlaxoSmithKline R&D UK [Ware, UK], Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), This work was supported by Telethon (SR-Tiget Core Grant 2011–2016) and Bioverativ sponsored research agreement., JAULIN, Nicolas, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Milani, M., Annoni, A., Moalli, F., Liu, T., Cesana, D., Calabria, A., Bartolaccini, S., Biffi, M., Russo, F., Visigalli, I., Raimondi, A., Patarroyo-White, S., Drager, D., Cristofori, P., Ayuso, E., Montini, E., Peters, R., Iannacone, M., Cantore, A., and Naldini, L.

Subjects
Kupffer Cells, [SDV]Life Sciences [q-bio], Phagocytosis, Genetic enhancement, Transgene, Genetic Vectors, CD47 Antigen, Article, Immune tolerance, Viral vector, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Immunity, Immune Tolerance, Animals, Humans, Medicine, Tissue Distribution, 030304 developmental biology, Phagocytes, 0303 health sciences, Innate immune system, business.industry, Lentivirus, Gene Transfer Techniques, Genetic Therapy, General Medicine, Immunity, Innate, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Liver, 030220 oncology & carcinogenesis, Immunology, Hepatocytes, Systemic administration, Macaca, business
Abstract

International audience; Liver-directed gene therapy for the coagulation disorder hemophilia showed safe and effective results in clinical trials using adeno-associated viral vectors to replace a functional coagulation factor, although some unmet needs remain. Lentiviral vectors (LVs) may address some of these hurdles because of their potential for stable expression and the low prevalence of preexisting viral immunity in humans. However, systemic LV administration to hemophilic dogs was associated to mild acute toxicity and low efficacy at the administered doses. Here, exploiting intravital microscopy and LV surface engineering, we report a major role of the human phagocytosis inhibitor CD47, incorporated into LV cell membrane, in protecting LVs from uptake by professional phagocytes and innate immune sensing, thus favoring biodistribution to hepatocytes after systemic administration. By enforcing high CD47 surface content, we generated phagocytosis-shielded LVs which, upon intravenous administration to nonhuman primates, showed selective liver and spleen targeting and enhanced hepatocyte gene transfer compared to parental LV, reaching supraphysiological activity of human coagulation factor IX, the protein encoded by the transgene, without signs of toxicity or clonal expansion of transduced cells.

Published
2019
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2. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy.

Author

Gentner B, Visigalli I, Hiramatsu H, Lechman E, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick JE, Biffi A, and Naldini L

Subjects
Animals, Cell Differentiation, Cell Separation, Cytoprotection, Galactosylceramidase metabolism, Gene Expression Regulation, Genes, Transgenic, Suicide, Hematopoietic Stem Cells cytology, Humans, Mice, Mice, SCID, MicroRNAs genetics, Organ Specificity genetics, Genetic Therapy, Hematopoietic Stem Cells metabolism, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell therapy, MicroRNAs metabolism
Abstract

Globoid cell leukodystrophy (GLD; also known as Krabbe disease) is an invariably fatal lysosomal storage disorder caused by mutations in the galactocerebrosidase (GALC) gene. Hematopoietic stem cell (HSC)-based gene therapy is being explored for GLD; however, we found that forced GALC expression was toxic to HSCs and early progenitors, highlighting the need for improved regulation of vector expression. We used a genetic reporter strategy based on lentiviral vectors to detect microRNA activity in hematopoietic cells at single-cell resolution. We report that miR-126 and miR-130a were expressed in HSCs and early progenitors from both mice and humans, but not in differentiated progeny. Moreover, repopulating HSCs could be purified solely on the basis of miRNA expression, providing a new method relevant for human HSC isolation. By incorporating miR-126 target sequences into a GALC-expressing vector, we suppressed GALC expression in HSCs while maintaining robust expression in mature hematopoietic cells. This approach protected HSCs from GALC toxicity and allowed successful treatment of a mouse GLD model, providing a rationale to explore HSC-based gene therapy for GLD.

Published
2010
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