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Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes

Author(s):

Michelle Fraga, Roselena Silvestri Schuh*, Édina Poletto, Talita Giacomet de Carvalho, Raqueli Teresinha França, Camila Vieira Pinheiro, Gilherme Baldo, Roberto Giugliani, Helder Ferreira Teixeira and Ursula Matte   Pages 1 - 8 ( 8 )

Abstract:


Background: Mucopolysaccharidosis type I (MPS I) is an inherited disorder caused by α-L-iduronidase (IDUA) deficiency. The available treatments are not effective in improving all signs and symptoms of the disease.

Objective: In the present study, we evaluated the transfection efficiency of repeated intravenous administrations of cationic nanoemulsions associated with the plasmid pIDUA (containing IDUA gene).

Methods: Cationic nanoemulsions were composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]-2000) (DSPE-PEG), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), medium chain triglycerides, glycerol, and water and were prepared by high-pressure homogenization and were repeatedly administered to MPS I mice for IDUA production and gene expression.

Results: A significant increase in IDUA expression was observed in all organs analyzed, and IDUA activity tended to increase with repeated administrations when compared to our previous report, when mice received a single administration of the same dose. In addition, GAGs were partially cleared from organs, as assessed through biochemical and histology analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed reduced presence of macrophage cells in treated than in untreated MPS I mice.

Conclusion: These set of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without significant increase in toxicity in the MPS I murine model.

Keywords:

Cationic nanoemulsions, gene therapy, mucopolysaccharidosis type I, nonviral vectors, plasmid.

Affiliation:

Curso de Farmácia, Área do Conhecimento de Ciências da Vida, Universidade de Caxias do Sul (UCS), Caxias do Sul, Programa de Pós-Graduação em Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Programa de Pós-Graduação em Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Centro de Terapia Gênica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Curso de Farmácia, Área do Conhecimento de Ciências da Vida, Universidade de Caxias do Sul (UCS), Caxias do Sul, Centro de Terapia Gênica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Centro de Terapia Gênica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Centro de Terapia Gênica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Programa de Pós-Graduação em Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre



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