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Perche Federico


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tél : 02.38.25.56.02 - fax : 02.38.25.78.07

Publications

2018   Références trouvées : 1

Van der Jeught K., De Koker S., Bialkowski L., Heirman C., Joe P. T., Perche F., Maenhout S., Bevers S., Broos K., Deswarte K., Malard V., Hammad H., Baril P., Benvegnu T., Jaffres P. A., Kooijmans S. A. A., Schiffelers R., Lienenklaus S., Midoux P., Pichon C., Breckpot K. and Thielemans K.  (2018)

Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-Cell Immunity with Improved Inflammatory Safety.

Acs Nano (2018) 12 (10) 9815-9829.
In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.

In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.


2012   Références trouvées : 1

Perche, F. Lambert, O. Berchel, M. Jaffrès, P.A. Pichon, C. Midoux, P.  (2012)

Gene transfer by histidylated lipopolyplexes : A dehydration method allowing preservation of their physicochemical parameters and transfection efficiency

International Journal of Pharmaceutics 423 (1) 144-150
Lipid-Polycation-DNA complexes (LPD) is a promising non-viral system for nucleic acids delivery. Usually, LPD are prepared just before their use. In the present work, we have examined whether dehydration of a new type of LPD (named LPD100) might be a storage option. LPD100 comprises PEGylated histidylated polylysine/pDNA polyplexes and a liposomal formulation made with lipophosphoramidates containing N-methylimidazolium and histamine polar heads. LPD100 were dehydrated by evaporation, and the physicochemical parameters and transfection efficiency (TE) of reconstituted LPD100 were compared to that of fresh LPD100. LPD100 previously dehydrated in the presence of 20% saccharose, displayed comparable size and surface charge as freshly prepared LPD100 but gave a better TE. CryoTEM experiments showed that the reconstituted LPD100 exhibited a shape similar to fresh ones. Moreover, when LPD100 were prepared with dehydrated pDNA/polymer complexes and fresh liposomes, TE was as efficient as with fresh LPD100 while a small increase of their size were observed. These results demonstrate that evaporation of LPD100 in the presence of saccharose is a powerful method to store them for a long period of time.

Lipid-Polycation-DNA complexes (LPD) is a promising non-viral system for nucleic acids delivery. Usually, LPD are prepared just before their use. In the present work, we have examined whether dehydration of a new type of LPD (named LPD100) might be a storage option. LPD100 comprises PEGylated histidylated polylysine/pDNA polyplexes and a liposomal formulation made with lipophosphoramidates containing N-methylimidazolium and histamine polar heads. LPD100 were dehydrated by evaporation, and the physicochemical parameters and transfection efficiency (TE) of reconstituted LPD100 were compared to that of fresh LPD100. LPD100 previously dehydrated in the presence of 20% saccharose, displayed comparable size and surface charge as freshly prepared LPD100 but gave a better TE. CryoTEM experiments showed that the reconstituted LPD100 exhibited a shape similar to fresh ones. Moreover, when LPD100 were prepared with dehydrated pDNA/polymer complexes and fresh liposomes, TE was as efficient as with fresh LPD100 while a small increase of their size were observed. These results demonstrate that evaporation of LPD100 in the presence of saccharose is a powerful method to store them for a long period of time.


2011   Références trouvées : 2

Perche, F., Benvegnu, T., Berchel, M., Lebègue, L., Pichon, C., Jaffrès, P.-A. & Midoux, P.,  (2011)

Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA

Nanomedicine : Nanotechnology, Biology and Medicine 7 (4) 445-453

Perche, F., Gosset, D., Mével, M., Miramon, M.-L., Yaouanc, J.J., Pichon, C., Benvegnu, T., Jaffrès, P.A. & Midoux, P.  (2011)

Selective delivery in dendritic cells with Mannosylated and Histidylated Lipopolyplexes.

J. Drug Target. 19 (5) 315-325


Mots-clés

Doctorant , Thérapies innovantes et nanomédecine