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

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

Volume: 21 Issue: 5

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

Affiliation:

• Centro de Terapia Genica, Servico de Pesquisa Experimental, Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre,Brazil

Keywords: Cationic nanoemulsions, gene therapy, mucopolysaccharidosis type I, nonviral vectors, plasmid, enzyme replacement therapy.

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.

Cite this article as:

Fraga Michelle , Schuh Silvestri Roselena *, Poletto Édina , de Carvalho Giacomet Talita , França Teresinha Raqueli , Pinheiro Vieira Camila , Baldo Gilherme , Giugliani Roberto , Teixeira Ferreira Helder and Matte Ursula , Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes, Current Gene Therapy 2021; 21 (5) . https://dx.doi.org/10.2174/1566523221666210126151420