Michelle Fraga1, Roselena Silvestri Schuh2, Édina Poletto2, Talita Giacomet de Carvalho2, Raqueli Teresinha França1, Camila Vieira Pinheiro2, Gilherme Baldo2, Roberto Giugliani2, Helder Ferreira Teixeira3, Ursula Matte2.
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 histological analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed a reduced presence of macrophage cells in treated than in untreated MPS I mice.
CONCLUSION: These sets of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without a significant increase in toxicity in the MPS I murine model. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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 histological analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed a reduced presence of macrophage cells in treated than in untreated MPS I mice.
CONCLUSION: These sets of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without a significant increase in toxicity in the MPS I murine model. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Entities:
Keywords:
Cationic nanoemulsions; enzyme replacementzzm321990therapy.; gene therapy; mucopolysaccharidosis type I; nonviral vectors; plasmid
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Substances：
Year: 2021
PMID： 33573568 DOI： 10.2174/1566523221666210126151420
Source DB: PubMed Journal: Curr Gene Ther ISSN： 1566-5232 Impact factor: 4.391